Therapeutic isoxazole compounds

ABSTRACT

The invention provides a compound of formula I: 
                         
wherein A 1 , A 2 , A 3 , R 1 , X, Y, and B have any of the values described herein, as well as salts of such compounds, compositions comprising such compounds, and therapeutic methods that comprise the administration of such compounds. The compounds are inhibitors of monoamine oxidase B (MAO-B) enzyme function and are useful for improving cognitive function and for treating psychiatric disorders in animals.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/198,686, filed Aug. 26, 2008, which claims priority under 35 U.S.C.§119(e) to U.S. Provisional Application No. 60/968,205, filed Aug. 27,2007; the disclosures of which are incorporated herein by reference intheir entireties.

BACKGROUND OF THE INVENTION

Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-dependent metabolicenzyme responsible for the oxidative deamination of both endogenous,aminergic neurotransmitters and xenobiotic amines. There are tworeported isoforms of MAO, MAO-A and MAO-B, which arise from twoindependent genes (Bach, et. al., Proc. Natl. Acad. Sci., 1988, 85,4934-4938). Both forms of MAO are distributed in a variety of tissues invarying amounts throughout the body; in the human brain, MAO-B ispresent to a greater extent then MAO-A (Saura, et. al., Neuroscience,1996, 70, 755-774).

MAO-A has greater selectivity for serotonin and adrenalin while MAO-B isselective for tyramine and phenethyl amine while both isoforms willmetabolize dopamine. Studies have shown that the level of MAO-B activityin the brain increases with age (Fowler, et. al., J. Neural Transm.,1980, 49, 1-20). The process of oxidative deamination, which producesboth peroxide and aldehydes as byproducts, has also been associated withan increase in oxidative damage in the brain, especially to dopaminergicneurons, potentially exacerbating the neuronal degeneration associatedwith diseases such as Alzheimer's Disease and Parkinson's Disease. Thereare also reports that the level of MAO-B activity present is greater inpatients with Alzheimer's disease which may be linked to the increasedcognitive impairment of Alzheimer patients (Dostert, et. al, Biochem.Pharmacol., 1989, 38, 555-561; and Emilsson, et. al., NeuroscienceLetters, 2002, 326, 56-60). This link between oxidative stress andprogression of neuronal damage suggests that inhibition of MAO-B willminimize the degenerative effects of both of these diseases, presumablyby preventing the metabolism of monoamines in the brain. Furthermore,the relative increase in dopamine levels, due to inhibition of itsmetabolism, may have effects on downstream regulation ofplasticity-associated cognitive function, which may help repair, notjust impede the progression of these diseases.

The use of selective MAO-B inhibitors for neurological diseases has beenknown for some time (Bentue-Ferrer, et. al., CNS Drugs, 1996, 6,217-236). Most early MAO inhibitors for the treatment of depression wereirreversible inhibitors with minimal selectivity for MAO-B versus MAO-A.This can be problematic due to potential side effects associated withboth the subsequent inability of the irreversibly inhibited enzyme toeffectively metabolize dietary amines associated with cardiovascularevents (the “cheese effect”) and the potential for drug-druginteractions with other drugs that are metabolized by MAO-B. More recentdrugs, including selegiline and rasagiline, while still irreversibleinhibitors, have greater selectivity for MAO-B, and have betterside-effect profiles (Chen & Swope, J Clin Pharmacol. 2005 45, 878-94).There is currently a need for compounds that are useful for enhancingcognitive function and for treating cognitive deterioration inParkinson's Disease and Alzheimer's Disease, as well as compounds thatcan generally improve cognition in normal, diseased, and aging subjects.Preferably, such agents will have higher potency and/or fewerside-effects than current therapies.

SUMMARY OF THE INVENTION

The invention provides MAO-B inhibiting compounds that are useful, forexample, for enhancing cognitive function in animals (e.g. humans).Accordingly, the invention provides a method for inhibiting one or moreMAO enzymes in an animal comprising administering to the animal aneffective MAO inhibiting amount of a compound of formula I.

Embodiments, Aspects and Variations of the Invention

The present disclosure provides the following embodiments, aspects andvariations: One embodiment provides a compound of formula I:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein:    -   R¹ is H (hydrogen), or is selected from the group consisting of        aryl and (C₁-C₆)alkyl, each optionally substituted with one or        more R_(h);    -   each R_(h) is independently selected from the group consisting        of halo, cyano, nitro, —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        —(CH₂)_(n)OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—,        (C₁-C₆)OC(O)—, and (C₁-C₆)C(O)O—;    -   A¹ is N (nitrogen), or CR²;    -   R² is H (hydrogen), (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,        (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or aryl optionally substituted        with one or more halo;    -   A² and A³ are each independently O (oxygen) or N (nitrogen) with        the proviso that when A² is O (oxygen), A³ is N (nitrogen) and        when A² is N (nitrogen), A³ is O (oxygen);    -   B is aryl or heteroaryl, each optionally substituted with one or        more R³;    -   X is —C(═O)—, —C(═S)—, —C(R⁴)₂—, or —S(O)_(z)—;    -   each n is independently an integer selected from 0, 1, and 2;    -   each z is independently an integer selected from 0, 1, and 2;    -   Y is R⁴, —N(R⁴)₂, —OR⁴, —SR⁴, or —C(R⁴)₃, each optionally        substituted with one or more R_(d);    -   each R⁴ is independently selected from the group consisting of        hydrogen, —OH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, (C₃-C₈)cycloalkyl,        —(CH₂)_(n)(C₃-C₈)cycloalkyl, heteroaryl, aryl, aryl(C₁-C₆)alkyl,        heterocycle, heterocycle(C₁-C₆)alkyl, heterocycle(C₁-C₆)alkanoyl        and NR_(a)R_(b); or when Y is —N(R⁴)₂, then two R⁴ groups are        optionally taken together with the nitrogen to which they are        attached to form a 3-8 membered monocyclic or a 7-12 membered        bicyclic ring system, each optionally comprising one or more        additional heteroatom groups selected from O (oxygen), S(O)_(z),        and NR_(c) wherein each ring system is optionally substituted        with one or more R_(d);    -   each R_(a) and R_(b) is independently hydrogen or (C₁-C₆)alkyl,        or R_(a) and R_(b) are optionally taken together with the        nitrogen to which they are attached to form a 3-8 membered        monocyclic or a 7-12 membered bicyclic ring system, each        optionally substituted with one or more C₁-C₆alkyl groups;    -   each R_(c) is independently selected from the group consisting        of hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl,        (C₁-C₆)alkylsulfonyl, aryl sulfonyl, (C₁-C₆)alkylC(O)—,        arylC(O)—, hydroxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, heterocycle,        (C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylaminocarbonyl, and        arylaminocarbonyl;    -   each R_(d) is independently halo, cyano, nitro, oxo,        R_(f)R_(g)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(f)R_(g),        —C(O)NR_(f)R_(g), —NR_(e)C(O)R_(g), arylC(O)NR_(f)R_(g),        —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_(n)OH,        (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—, (C₁-C₆)OC(O)—,        (C₁-C₆)C(O)O—, heterocycle, aryl, heterocycle(C₁-C₆)alkyl,        aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl,        —NR_(e)S(O)_(z)aryl, —NR_(e)C(O)NR_(f)R_(g), —NR_(e)C(O)OR_(f),        or —OC(O)NR_(f)R_(g);    -   each R_(e) is independently hydrogen, (C₁-C₆)alkyl, aryl or        heteroaryl;    -   each R_(f) and R_(g) is independently hydrogen, (C₁-C₆)alkyl,        aryl or heteroaryl, or R_(f) and R_(g) are optionally taken        together with the nitrogen to which they are attached to form a        3-8 membered monocyclic or a 7-12 membered bicyclic ring system,        each optionally comprising one or more additional heteroatom        groups selected from O (oxygen), S(O)_(z), and NR_(c) wherein        each ring system is optionally substituted with one or more        R_(q);    -   each R_(q) is independently halo, cyano, nitro, oxo,        R_(i)R_(j)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(i)R_(j),        —C(O)NR_(i)R_(j), —NR_(k)C(O)R_(j), arylC(O)NR_(i)R_(j),        —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_(n)OH,        (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—, (C₁-C₆)OC(O)—,        (C₁-C₆)C(O)O—, heterocycle, aryl, heterocycle(C₁-C₆)alkyl,        aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl,        —NR_(k)S(O)_(z)aryl, —NR_(k)C(O)NR_(i)R_(j), —NR_(k)C(O)OR_(i),        or —OC(O)NR_(i)R_(j);    -   each R_(k) is independently hydrogen, (C₁-C₆)alkyl, aryl or        heteroaryl;    -   each R_(i) and R_(j) is independently hydrogen, (C₁-C₆)alkyl,        aryl or heteroaryl;    -   each R³ is (C₁-C₆)alkyl, —NR_(i)R_(j), —C(O)NR_(i)R_(j), or        aryl(C₁-C₆)alkyl; and    -   the dashed line represents an optional double bond wherein the        ring comprising A¹, A², and A³ is heteroaromatic;    -   with the proviso that the compound of formula I is not selected        from the group consisting of:

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula I. Another embodiment includes the        compound of formula I, wherein each R³ can be independently        (C₁-C₆)alkyl, or aryl(C₁-C₆)alkyl. Another embodiment includes        the compound of formula I, wherein each R_(h) can be halo,        cyano, nitro, —OH, or (C₁-C₆)alkyl. In some embodiments R_(h)        can be fluoro.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula I.

Another embodiment includes the compound of formula I with the provisothat when B is a 5-membered ring and Y is —N(R⁴)₂, then R⁴ is not a7-azabicyclo[2.2.1]heptane or 1-azabicyclo[2.2.2]octane, each optionallysubstituted with (C₁-C₆)alkyl. Another embodiment includes the compoundof formula I with the proviso that when B is a 5-membered ring, then R³is not —C(O)NR_(i)R_(j).

Another embodiment includes the compound of formula I with the provisothat when B is thiophene and not substituted with R³, X is —C(═O)—, Y is—N(R⁴)₂, and one R⁴ is H, then the other R⁴ is not —OH; and

-   -   when B is thiophene and not substituted with R³, and X is        —C(═O)—, then Y is not —OH, or —O(C₁-C₆)alkyl.

Another embodiment includes the compound of formula I having formula Ia:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein:    -   Z¹, Z², and Z³ are each independently O (oxygen), N (nitrogen),        S (sulfur), or CR⁵ O (oxygen), N (nitrogen), S (sulfur), or CR⁵        with the proviso that at least one of Z¹, Z², and Z³ is not CR⁵;    -   each R⁵ is independently H (hydrogen), (C₁-C₆)alkyl,        —NR_(f)R_(g), —C(O)NR_(f)R_(g), or aryl(C₁-C₆)alkyl;    -   each R_(f) and R_(g) is independently hydrogen, (C₁-C₆)alkyl,        aryl or heteroaryl, or R_(f) and R_(g) are optionally taken        together with the nitrogen to which they are attached to form a        3-8 membered monocyclic or a 7-12 membered bicyclic ring system,        each optionally comprising one or more additional heteroatom        groups selected from O (oxygen), S(O)_(z), and NR_(c) wherein        each ring system is optionally substituted with one or more        R_(q);    -   each R_(q) is independently halo, hydroxy, cyano, nitro, oxo,        COOH, —NR_(i)R_(j), R_(i)R_(j)N(C₁-C₆)alkyl, —(CH₂)—NR_(i)R_(j),        —C(O)NR_(i)R_(j), —NR_(k)C(O)R_(i), arylC(O)NR_(i)R_(j),        —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_(n)OH,        (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—, (C₁-C₆)OC(O)—,        (C₁-C₆)C(O)O—, heterocycle, aryl, heterocycle(C₁-C₆)alkyl,        aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl,        —NR_(k)S(O)_(z)aryl, —NR_(k)C(O)NR_(i)R_(j), —NR_(k)C(O)OR_(i),        or —OC(O)NR_(i)R_(j);    -   each R_(e) is independently selected from the group consisting        of hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl, (C₁-C₆)alkyl        sulfonyl, aryl sulfonyl, (C₁-C₆)alkylC(O)—, arylC(O)—,        hydroxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, heterocycle,        (C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylaminocarbonyl, and        arylaminocarbonyl;    -   each n is independently an integer selected from 0, 1, and 2;    -   each z is independently an integer selected from 0, 1, and 2;    -   each R_(k) is independently hydrogen, (C₁-C₆)alkyl, aryl or        heteroaryl;    -   each R_(i) and R_(j) is independently hydrogen, (C₁-C₆)alkyl,        aryl or heteroaryl;    -   R¹, A¹, A², A³, X and Y are defined according to the definitions        for the compound of formula I; and    -   the dashed line represents an optional double bond wherein the        ring comprising Z¹, Z², and Z³ is heteroaromatic.

In some embodiments Z¹ can be O (oxygen), N (nitrogen) or S (sulfur). Insome embodiments Z² can be O (oxygen), N (nitrogen) S (sulfur), or CR⁵.In some embodiments Z³ can be O (oxygen), N (nitrogen) S (sulfur), orCR⁵.

Another embodiment includes a compound of formula Ia with the provisothat when Z¹ is O (oxygen), N (nitrogen) or S (sulfur) and Y is —N(R⁴)₂,then R⁴ is not a 7-azabicyclo[2.2.1]heptane or1-azabicyclo[2.2.2]octane, each optionally substituted with(C₁-C₆)alkyl. Another embodiment includes a compound of formula Ia withthe proviso that when Z¹ is S (sulfur), then Z³ is not CR⁵ where R⁵ is—C(O)NR_(i)R_(j).

Another embodiment includes a compound of formula Ia, wherein Z¹ is S(sulfur). Another embodiment includes a compound of formula Ia, whereinX is —C(═O). Another embodiment includes the compound of formula Ia,wherein each R_(h) can be halo, cyano, nitro, —OH, or (C₁-C₆)alkyl. Insome embodiments R_(h) can be fluoro.

Another embodiment includes the compound of formula Ia with the provisothat when Z¹ is S (sulfur) and Z² and Z³ are both CR⁵ where each R⁵ is H(hydrogen), X is —C(═O)—, Y is —N(R⁴)₂, and one R⁴ is H, then the otherR⁴ is not —OH; and when Z¹ is S (sulfur) and Z² and Z³ are both CR⁵where each R⁵ is H, and X is —C(═O)—, then Y is not —OH, or—O(C₁-C₆)alkyl. Another embodiment includes the compound of formula Iawith the proviso that when Z¹ is S (sulfur) and Z² is CR⁵ where R⁵ is H(hydrogen), X is —C(═O)—, Y is —N(R⁴)₂, and one R⁴ is H, then the otherR⁴ is not —OH; and when Z¹ is S (sulfur) and Z² is CR⁵ where R⁵ is H,and X is —C(═O)—, then Y is not —OH, or —O(C₁-C₆)alkyl. Anotherembodiment includes the compound of formula Ia with the proviso thatwhen Z¹ is S (sulfur) and Z³ is CR⁵ where R⁵ is H (hydrogen), X is—C(═O)—, Y is —N(R⁴)₂, and one R⁴ is H, then the other R⁴ is not —OH;and when Z¹ is S (sulfur) and Z³ is CR⁵ where R⁵ is H, and X is —C(═O)—,then Y is not —OH, or —O(C₁-C₆)alkyl.

Another embodiment includes the compound of formula Ia, wherein Y is—N(R⁴)₂. In some embodiments, —N(R⁴)₂ is piperidinyl optionallysubstituted with one or more R_(d).

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula Ia.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula Ia.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula Ia.

Another embodiment includes the compound of formula I having the formulaIIa:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein:    -   R¹ is H (hydrogen), or is selected from the group consisting of        aryl and (C₁-C₆)alkyl, each optionally substituted with one or        more R_(h);    -   each R_(h) is independently selected from the group consisting        of halo, cyano, nitro, —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        —(CH₂)_(n)OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—,        (C₁-C₆)OC(O)—, and (C₁-C₆)C(O)O—;    -   A¹ is N (nitrogen), or CR²;    -   R² is H (hydrogen), (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,        (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or aryl optionally substituted        with one or more halo;    -   A² and A³ are each independently O (oxygen) or N (nitrogen) with        the proviso that when A² is O (oxygen), A³ is N (nitrogen) and        when A² is N (nitrogen), A³ is O (oxygen);    -   Z¹, Z², and Z³ are each independently O (oxygen), N (nitrogen),        S (sulfur), or CR⁵ with the proviso that at least one of Z¹, Z²,        and Z³ is not CR⁵;    -   each R⁵ is independently H (hydrogen), (C₁-C₆)alkyl,        —NR_(i)R_(j), —C(O)NR_(i)R_(j), or aryl(C₁-C₆)alkyl;    -   X is —C(═O)—, —C(═S)—, —C(R⁴)₂—, or —S(O)_(z)—;    -   each n is independently an integer selected from 0, 1, and 2;    -   each z is independently an integer selected from 0, 1, and 2;    -   Y is —N(R⁴)₂ optionally substituted with one or more R_(d);    -   each R⁴ is independently selected from the group consisting of        hydrogen, —OH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, (C₃-C₈)cycloalkyl,        —(CH₂)_(n)(C₃-C₈)cycloalkyl, heteroaryl, aryl, aryl(C₁-C₆)alkyl,        heterocycle, heterocycle(C₁-C₆)alkyl, heterocycle(C₁-C₆)alkanoyl        and NR_(a)R_(b); or two R⁴ groups are optionally taken together        with the nitrogen to which they are attached to form a 3-8        membered monocyclic or a 7-12 membered bicyclic ring system,        each optionally comprising one or more additional heteroatom        groups selected from O (oxygen), S(O)_(z), and NR_(c) wherein        each ring system is optionally substituted with one or more        R_(d);    -   each R_(a) and R_(b) is independently hydrogen or (C₁-C₆)alkyl,        or R_(a) and R_(b) are optionally taken together with the        nitrogen to which they are attached to form a 3-8 membered        monocyclic or a 7-12 membered bicyclic ring system, each        optionally substituted with one or more C₁-C₆alkyl groups;    -   each R_(c) is independently selected from the group consisting        of hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl,        (C₁-C₆)alkylsulfonyl, aryl sulfonyl, (C₁-C₆)alkylC(O)—,        arylC(O)—, hydroxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, heterocycle,        (C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylaminocarbonyl, and        arylaminocarbonyl;    -   each R_(d) is independently halo, cyano, nitro, oxo,        R_(f)R_(g)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(f)R_(g),        —C(O)NR_(f)R_(g), —NR_(e)C(O)R_(g), arylC(O)NR_(f)R_(g),        —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_(n)OH,        (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—, (C₁-C₆)OC(O)—,        (C₁-C₆)C(O)O—, heterocycle, aryl, heterocycle(C₁-C₆)alkyl,        aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl,        —NR_(e)S(O)_(z)aryl, —NR_(e)C(O)NR_(f)R_(g), —NR_(e)C(O)OR_(f),        or —OC(O)NR_(f)R_(g);    -   each R_(e) is independently hydrogen, (C₁-C₆)alkyl, aryl or        heteroaryl;    -   each R_(f) and R_(g) is independently hydrogen, (C₁-C₆)alkyl,        aryl or heteroaryl, or R_(f) and R_(g) are optionally taken        together with the nitrogen to which they are attached to form a        3-8 membered monocyclic or a 7-12 membered bicyclic ring system,        each optionally comprising one or more additional heteroatom        groups selected from O (oxygen), S(O)_(z), and NR_(c) wherein        each ring system is optionally substituted with one or more        R_(q);    -   each R_(q) is independently halo, cyano, nitro, oxo,        R_(i)R_(j)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(i)R_(j),        —C(O)NR_(i)R_(j), —NR_(k)C(O)R_(i), arylC(O)NR_(i)R_(j),        —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_(n)OH,        (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—, (C₁-C₆)OC(O)—,        (C₁-C₆)C(O)O—, heterocycle, aryl, heterocycle(C₁-C₆)alkyl,        aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl,        —NR_(k)S(O)_(z)aryl, —NR_(k)C(O)NR_(i)R_(j), —NR_(k)C(O)OR_(i),        or —OC(O)NR_(i)R_(j);    -   each R_(k) is independently hydrogen, (C₁-C₆)alkyl, aryl or        heteroaryl;    -   each R_(i) and R_(j) is independently hydrogen, (C₁-C₆)alkyl,        aryl or heteroaryl; and    -   the dashed line represents an optional double bond wherein the        ring comprising A¹, A², and A³ is heteroaromatic and the ring        comprising Z¹, Z², and Z³ is heteroaromatic;    -   with the proviso that the compound of formula IIa is not        selected from the group consisting of:

In some embodiments Z¹ can be O (oxygen), N (nitrogen) or S (sulfur). Insome embodiments Z² can be O (oxygen), N (nitrogen) S (sulfur), or CR⁵.In some embodiments Z³ can be O (oxygen), N (nitrogen) S (sulfur), orCR⁵. In a typical embodiment, Z¹ can be S (sulfur), Z² can be CR⁵ and Z³can be CR⁵.

Another embodiment includes the compound of formula IIa with the provisothat when Z¹ is O (oxygen), N (nitrogen) or S (sulfur), then R⁴ is not a7-azabicyclo[2.2.1]heptane or 1-azabicyclo[2.2.2]octane, each optionallysubstituted with (C₁-C₆)alkyl. Another embodiment includes the compoundof formula IIa with the proviso that, Z³ is not CR⁵ where R⁵ is—C(O)NR_(i)R_(j). Another embodiment includes the compound of formulaIIa with the proviso that when Z¹ is S (sulfur) and Z² and Z³ are bothCR⁵ where each R⁵ is H, X is —C(═O)—, Y is —N(R⁴)₂, and one R⁴ is H,then the other R⁴ is not —OH; and when Z¹ is S (sulfur) and Z² and Z³are both CR⁵ where each R⁵ is H, and X is —C(═O)—, then Y is not —OH, or—O(C₁-C₆)alkyl. Another embodiment includes the compound of formula IIawherein —N(R⁴)₂ is piperidinyl optionally substituted with one or moreR_(d). Another embodiment includes the compound of formula IIa, whereineach R_(h) can be halo, cyano, nitro, —OH, or (C₁-C₆)alkyl. In someembodiments R_(h) can be fluoro.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula IIa.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula IIa.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula IIa.

Another embodiment includes the compound of formula IIa selected fromthe group consisting of:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof.

Another embodiment includes the compound of formula I having the formulaId:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein:    -   R¹ is H (hydrogen), or is selected from the group consisting of        aryl and (C₁-C₆)alkyl, each optionally substituted with one or        more R_(h);    -   each R_(h) is independently selected from the group consisting        of halo, cyano, nitro, —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        —(CH₂)_(n)OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—,        (C₁-C₆)OC(O)—, and (C₁-C₆)C(O)O—;    -   A¹ is N (nitrogen), or CR²;    -   R² is H (hydrogen), (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,        (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or aryl optionally substituted        with one or more halo;    -   A² and A³ are each independently O (oxygen) or N (nitrogen) with        the proviso that when A² is O (oxygen), A³ is N (nitrogen) and        when A² is N (nitrogen), A³ is O (oxygen);    -   Z¹, Z², and Z³ are each independently is O (oxygen), N        (nitrogen), S (sulfur), or CR⁵ with the proviso that at least        one of Z¹, Z², and Z³ is not CR⁵;    -   Z² is O, N (nitrogen), S (sulfur), or CR⁵;    -   Z³ is O, N (nitrogen), S (sulfur), or CR⁵;    -   each R⁵ is independently H (hydrogen), (C₁-C₆)alkyl,        —NR_(i)R_(j), —C(O)NR_(i)R_(j), or aryl(C₁-C₆)alkyl;    -   each R⁴ is independently selected from the group consisting of        hydrogen, —OH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, (C₃-C₈)cycloalkyl,        —(CH₂)_(n)(C₃-C₈)cycloalkyl, heteroaryl, aryl, aryl(C₁-C₆)alkyl,        heterocycle, heterocycle(C₁-C₆)alkyl, heterocycle(C₁-C₆)alkanoyl        and NR_(a)R_(b), each optionally substituted with one or more        R_(d);    -   each R_(a) and R_(b) is independently hydrogen or (C₁-C₆)alkyl,        or R_(a) and R_(b) are optionally taken together with the        nitrogen to which they are attached to form a 3-8 membered        monocyclic or a 7-12 membered bicyclic ring system, each        optionally substituted with one or more C₁-C₆alkyl groups;    -   each R_(d) is independently halo, cyano, nitro, oxo,        R_(f)R_(g)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(f)R_(g),        —C(O)NR_(f)R_(g), —NR_(e)C(O)R_(g), arylC(O)NR_(f)R_(g),        —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_(n)OH,        (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—, (C₁-C₆)OC(O)—,        (C₁-C₆)C(O)O—, heterocycle, aryl, heterocycle(C₁-C₆)alkyl,        aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl,        —NR_(e)S(O)_(z)aryl, —NR_(e)C(O)NR_(f)R_(g), —NR_(e)C(O)OR_(f),        or —OC(O)NR_(f)R_(g);    -   each n is independently an integer selected from 0, 1, and 2;    -   each z is independently an integer selected from 0, 1, and 2;    -   each R_(e) is independently hydrogen, (C₁-C₆)alkyl, aryl or        heteroaryl;    -   each R_(f) and R_(g) is independently hydrogen, (C₁-C₆)alkyl,        aryl or heteroaryl, or R_(f) and R_(g) are optionally taken        together with the nitrogen to which they are attached to form a        3-8 membered monocyclic or a 7-12 membered bicyclic ring system,        each optionally comprising one or more additional heteroatom        groups selected from O (oxygen), S(O)_(z), and NR_(c) wherein        each ring system is optionally substituted with one or more        R_(q);    -   each R_(q) is independently halo, cyano, nitro, oxo,        R_(i)R_(j)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(i)R_(j),        —C(O)NR_(i)R_(j), —NR_(k)C(O)R_(i), arylC(O)NR_(i)R_(j),        —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_(n)OH,        (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—, (C₁-C₆)OC(O)—,        (C₁-C₆)C(O)O—, heterocycle, aryl, heterocycle(C₁-C₆)alkyl,        aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl,        —NR_(k)S(O)_(z)aryl, —NR_(k)C(O)NR_(i)R_(j), —NR_(k)C(O)OR_(i),        or —OC(O)NR_(i)R_(j);    -   each R_(k) is independently hydrogen, (C₁-C₆)alkyl, aryl or        heteroaryl;    -   each R_(i) and R_(j) is independently hydrogen, (C₁-C₆)alkyl,        aryl or heteroaryl; and    -   the dashed line represents an optional double bond wherein the        ring comprising A¹, A², and A³ is heteroaromatic and the ring        comprising Z¹, Z², and Z³ is heteroaromatic.

In some embodiments Z¹ can be O (oxygen), N (nitrogen) or S (sulfur). Insome embodiments Z² can be O (oxygen), N (nitrogen) S (sulfur), or CR⁵.In some embodiments Z³ can be O (oxygen), N (nitrogen) S (sulfur), orCR⁵. In a typical embodiment, Z¹ can be S (sulfur), Z² can be CR⁵ and Z³can be CR⁵. Another embodiment includes the compound of formula Id,wherein each R_(h) can be halo, cyano, nitro, —OH, or (C₁-C₆)alkyl. Insome embodiments R_(h) can be fluoro.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula Ia.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula Id.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula Id.

Another embodiment includes the compound of formula I having the formulaIe:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein:    -   R¹ is H (hydrogen), or is selected from the group consisting of        (C₁-C₆)alkyl and aryl, each optionally substituted with one or        more R_(h);    -   each R_(h) is independently selected from the group consisting        of halo, cyano, nitro, —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        —(CH₂)_(n)OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—,        (C₁-C₆)OC(O)—, and (C₁-C₆)C(O)O—;    -   A¹ is N (nitrogen), or CR²;    -   R² is H (hydrogen), (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,        (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or aryl optionally substituted        with one or more halo;    -   A² and A³ are each independently O (oxygen) or N (nitrogen) with        the proviso that when A² is O (oxygen), A³ is N (nitrogen) and        when A² is N (nitrogen), A³ is O (oxygen);    -   Z¹ is N (nitrogen), or CR⁵;    -   Z² is N (nitrogen), or CR⁵;    -   Z³ is N (nitrogen), or CR⁵;    -   Z⁴ is N (nitrogen), or CR⁵;    -   each R⁵ is independently H, (C₁-C₆)alkyl, —NR_(i)R_(j),        —C(O)NR_(i)R_(j), or aryl(C₁-C₆)alkyl;    -   X is —C(═O)—, —C(═S)—, —C(R⁴)₂—, or —S(O)_(z)—;    -   each n is independently an integer selected from 0, 1, and 2;    -   each z is independently an integer selected from 0, 1, and 2;    -   Y is R⁴, —N(R⁴)₂, —OR⁴, —SR⁴, or —C(R⁴)₃, each optionally        substituted with one or more R_(d);    -   each R⁴ is independently selected from the group consisting of        hydrogen, —OH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, (C₃-C₈)cycloalkyl,        —(CH₂)_(n)(C₃-C₈)cycloalkyl, heteroaryl, aryl, aryl(C₁-C₆)alkyl,        heterocycle, heterocycle(C₁-C₆)alkyl, heterocycle(C₁-C₆)alkanoyl        and NR_(a)R_(b); or when Y is —N(R⁴)₂, then two R⁴ groups are        optionally taken together with the nitrogen to which they are        attached to form a 3-8 membered monocyclic or a 7-12 membered        bicyclic ring system, each optionally comprising one or more        additional heteroatom groups selected from O (oxygen), S(O)_(z),        and NR_(c) wherein each ring system is optionally substituted        with one or more R_(d);    -   each R_(a) and R_(b) is independently hydrogen or (C₁-C₆)alkyl,        or R_(a) and R_(b) are optionally taken together with the        nitrogen to which they are attached to form a 3-8 membered        monocyclic or a 7-12 membered bicyclic ring system, each        optionally substituted with one or more C₁-C₆alkyl groups;    -   each R_(c) is independently selected from the group consisting        of hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl,        (C₁-C₆)alkylsulfonyl, arylsulfonyl, (C₁-C₆)alkylC(O)—,        arylC(O)—, hydroxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, heterocycle,        (C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylaminocarbonyl, and        arylaminocarbonyl;    -   each R_(d) is independently halo, cyano, nitro, oxo,        R_(f)R_(g)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(f)R_(g),        —C(O)NR_(f)R_(g), —NR_(e)C(O)R_(g), arylC(O)NR_(f)R_(g),        —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_(n)OH,        (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—, (C₁-C₆)OC(O)—,        (C₁-C₆)C(O)O—, heterocycle, aryl, heterocycle(C₁-C₆)alkyl,        aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl,        —NR_(e)S(O)_(z)aryl, —NR_(e)C(O)NR_(f)R_(g), —NR_(e)C(O)OR_(f),        or —OC(O)NR_(f)R_(g);    -   each R_(e) is independently hydrogen, (C₁-C₆)alkyl, aryl or        heteroaryl;    -   each R_(f) and R_(g) is independently hydrogen, (C₁-C₆)alkyl,        aryl or heteroaryl, or R_(f) and R_(g) are optionally taken        together with the nitrogen to which they are attached to form a        3-8 membered monocyclic or a 7-12 membered bicyclic ring system,        each optionally comprising one or more additional heteroatom        groups selected from O (oxygen), S(O)_(z), and NR_(c) wherein        each ring system is optionally substituted with one or more        R_(q);    -   each R_(q) is independently halo, cyano, nitro, oxo,        R_(i)R_(j)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(i)R_(j),        —C(O)NR_(i)R_(j), —NR_(k)C(O)R_(i), arylC(O)NR_(i)R_(j),        —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)^(n)OH,        (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)C(O)—, (C₁-C₆)OC(O)—,        (C₁-C₆)C(O)O—, heterocycle, aryl, heterocycle(C₁-C₆)alkyl,        aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl,        —NR_(k)S(O)_(z)aryl, —NR_(k)C(O)NR_(i)R_(j), —NR_(k)C(O)OR_(i),        or —OC(O)NR_(i)R_(j);    -   each R_(k) is independently hydrogen, (C₁-C₆)alkyl, aryl or        heteroaryl;    -   each R_(i) and R_(j) is independently hydrogen, (C₁-C₆)alkyl,        aryl or heteroaryl; and    -   the dashed line represents an optional double bond wherein the        ring comprising A¹, A², and A³ is heteroaromatic and the ring        comprising Z¹, Z², Z³ and Z⁴ is aromatic or heteroaromatic    -   with the proviso that the compound of Formula Ie is not selected        from the group consisting of:

Another embodiment includes the compound of formula Ie wherein Z¹, Z²,Z³ and Z⁴ can each be CR⁵. Another embodiment includes the compound offormula Ie wherein Y can be —N(R⁴)₂. Another embodiment includes thecompound of formula Ie wherein Z¹, Z², Z³ and Z⁴ can each be CR⁵ and Ycan be —N(R⁴)₂. Another embodiment includes the compound of formula Ie,wherein each R_(h) can be halo, cyano, nitro, —OH, or (C₁-C₆)alkyl. Insome embodiments R_(h) can be fluoro.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula Ie.

Another embodiment includes the compound of formula Ie selected from thegroup consisting of

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula Ie. In some embodiments, Y can be        —N(R⁴)₂ and X can be —C(═O)—. In some embodiments, R¹ can be CF₃        and A¹ can be CR².

Another embodiment includes the compound of formula Ie, wherein Z¹, Z²,Z³ and Z⁴ can each be CR⁵, Y can be —N(R⁴)₂, and X can be —C(═O)—.Another embodiment includes the compound of formula Ie, wherein Y can be—C(R⁴)₃ and X can be —C(═O)—. Another embodiment includes the compoundof formula Ie wherein Y can be —C(R⁴)₃, X can be —C(═O)— and Z¹, Z², Z³and Z⁴ can each be CR⁵.

Another embodiment includes a compound having the formula:

-   -   or a pharmaceutically acceptable salt or prodrug ester thereof,    -   wherein the variables are defined according to the definitions        for the compound of formula Ie.

One embodiment of the invention provides a pharmaceutical compositioncomprising:

-   -   a) the compound of any of the embodiments and examples disclosed        herein; and    -   b) a pharmaceutically acceptable carrier.

The present embodiments provide for a method of preparing apharmaceutically acceptable salt of the compound of any of theembodiments and examples disclosed herein, comprising:

-   -   a) deprotecting a corresponding compound that comprises one or        more protecting groups to provide the compound; and    -   b) forming a pharmaceutically acceptable salt from the compound.

The present embodiments provide for a method of inhibiting one or moremonoamine oxidase (MAO) enzymes in an animal comprising administering tothe animal an effective amount of a compound of any of the embodimentsand examples disclosed herein. In some embodiments, the animal is ahealthy animal. In some embodiments, the animal is an aged animal.

The present embodiments provide for a method for improving cognitivefunction in an animal in need of such treatment comprising administeringto the animal an effective amount of a compound of any of theembodiments and examples disclosed herein. In some embodiments, theanimal can be a healthy animal. In some embodiments, the animal can bean aged animal.

The present embodiments provide for a method for activating the CREBpathway in an animal in need of such treatment, comprising administeringto the animal an effective amount of a compound of compound of any ofthe embodiments and examples disclosed herein.

The present embodiments provide for a method for treating age-associatedmemory impairment, mild cognitive impairment, Alzheimer's disease orParkinson's disease in an animal in need of such treatment comprisingadministering to the animal an effective amount of a compound of any ofthe embodiments and examples disclosed herein. In some embodiments, theanimal can have a psychiatric disorder. In some embodiments, thepsychiatric disorder can be a psychotic disorder, a neurologicaldisorder, or a neurotic disorder. In some embodiments, the psychoticdisorder can be schizophrenia. In some embodiments, the animal can havea disorder of the central nervous system. In some embodiments, theanimal can have head trauma, brain trauma or cerebrovascular disease. Insome embodiments, the cerebrovascular disease can be vascular dementia.In some embodiments, the animal can have attention deficit disorder. Insome embodiments, the animal has an affective disorder thecerebrovascular disease is vascular dementia the mild cognitiveimpairment is associated with depression.

The present embodiments provide for a method for treating a psychiatricdisorder in an animal comprising administering to an animal in needthereof an effective amount of a compound of any of the embodiments andexamples disclosed herein. In some embodiments, the psychiatric disordercan be a disorder of the central nervous system. In some embodiments,the disorder of the central nervous system can be age-associated memoryimpairment, mild cognitive impairment, Alzheimer's disease orParkinson's disease. In some embodiments, the psychiatric disorder canbe associated with head trauma, brain trauma or cerebrovascular disease.In some embodiments, the psychiatric disorder can be attention deficitdisorder. In some embodiments, the psychiatric disorder can be anaffective disorder. In some embodiments, the cerebrovascular disease canbe vascular dementia. In some embodiments, the psychiatric disorder canbe depression.

The present embodiments provide for a use of a compound of any ofcompound of any of the embodiments and examples disclosed herein, or apharmaceutically acceptable salt or prodrug ester thereof, for themanufacture of a medicament useful for improving cognitive function inan animal.

The present embodiments provide for a use of a compound of any of theembodiments and examples disclosed herein, or a pharmaceuticallyacceptable salt or prodrug ester thereof, for the manufacture of amedicament useful for inhibiting MAO receptors in an animal.

The present embodiments provide for a use of a compound of any of theembodiments and examples disclosed herein, or a pharmaceuticallyacceptable salt or prodrug ester thereof, for the manufacture of amedicament useful for activating the CREB pathway in an animal.

The present embodiments provide for a use of a compound of any of theembodiments and examples disclosed herein, or a pharmaceuticallyacceptable salt or prodrug ester thereof, for the manufacture of amedicament useful for treating a psychiatric disorder in an animal.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, common organic abbreviations are defined as follows:

Ac Acetyl

aq. Aqueous

Bu n-Butyl

cat. Catalytic

CDI 1,1′-carbonyldiimidazole

° C. Temperature in degrees Centigrade

Dowtherm® eutectic mixture of diphenyl ether and biphenyl

DBN 1,5-Diazabicyclo[4.3.0]non-5-ene

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DIEA Diisopropylethylamine

DMA Dimethylacetamide

DMF N,N′-Dimethylformamide

DMSO Dimethylsulfoxide

Et Ethyl

g Gram(s)

h Hour (hours)

HPLC High performance liquid chromatography

iPr or isopr Isopropyl

LCMS Liquid chromatography-mass spectrometry

Me Methyl

MeOH Methanol

mL Milliliter(s)

Pd/C Palladium on activated carbon

ppt Precipitate

rt Room temperature

TEA Triethylamine

Tert, t tertiary

THF tetrahydrofuran

μL Microliter(s)

The term “halo” used herein refers to fluoro, chloro, bromo, or iodo. Asused herein, the term “alkyl” refers to an aliphatic hydrocarbon group.The alkyl moiety may or may not be a “saturated alkyl” group, i.e., onethat does not contain any alkene or alkyne moieties. An “alkene” moietyrefers to a group consisting of at least two carbon atoms and at leastone carbon-carbon double bond, and an “alkyne” moiety refers to a groupconsisting of at least two carbon atoms and at least one carbon-carbontriple bond. The alkyl moiety may be branched, straight chain, orcyclic. Examples of branched alkyl groups include, but are not limitedto, isopropyl, sec-butyl, t-butyl and the like. Examples of straightchain alkyl groups include, but are not limited to, methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, and the like. Examples ofcycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term “alkoxy” used herein refers to straight or branched chain alkylradical covalently bonded to the parent molecule through an —O— linkage.Examples of alkoxy groups include, but are not limited to, methoxy,ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy andthe like.

The term “alkoxycarbonyl” used herein refers to an alkoxy radicalcovalently bonded to the parent molecule through a carbonyl linkage.Examples of alkoxycarbonyl groups include, but are not limited to,methylOC(O)—, ethylOC(O)—, propylOC(O)—, isopropylOC(O)—, butylOC(O)—,n-butylOC(O)—, sec-butylOC(O)—, t-butylOC(O)— and the like.

The term “alkenyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon double bond including, but not limited to, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

The term “alkynyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon triple bond including, but not limited to, 1-propynyl, 1-butynyl,2-butynyl, and the like.

The term “aryl” used herein refers to homocyclic aromatic radicalwhether one ring or multiple fused rings. Moreover, the term “aryl”includes fused ring systems wherein at least two aryl rings, or at leastone aryl and an ortho-fused bicyclic carbocyclic radical having aboutnine to ten ring atoms in which at least one ring is aromatic share atleast one chemical bond. Examples of “aryl” rings include, but are notlimited to, optionally substituted phenyl, biphenyl, naphthalenyl,phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.

The term, “heterocycle” or “heterocycle group” used herein refers to anoptionally substituted monocyclic, bicyclic, or tricyclic ring systemcomprising at least one heteroatom in the ring system backbone. Theheteroatoms are independently selected from oxygen, sulfur, andnitrogen. The term, “heterocycle” includes multiple fused ring systems.Moreover, the term “heterocycle” includes fused ring systems that mayhave any degree of saturation provided that at least one ring in thering system is not aromatic. The monocyclic, bicyclic, or tricyclic ringsystem may be substituted or unsubstituted, and can be attached to othergroups via any available valence, preferably any available carbon ornitrogen. Preferred monocyclic ring systems are of 3 to 8 members. Sixmembered monocyclic rings contain from up to three heteroatoms whereineach heteroatom is individually selected from oxygen, sulfur, andnitrogen, and wherein when the ring is five membered, preferably it hasone or two heteroatoms wherein each heteroatom is individually selectedfrom oxygen, sulfur, and nitrogen. Preferred bicyclic cyclic ringsystems are of 7 to 12 members and include spirocycles. An example of anoptional substituent includes, but is not limited to, oxo (═O).

The term “heteroaryl” used herein refers to an aromatic heterocyclicgroup, whether one ring or multiple fused rings. In fused ring systems,the one or more heteroatoms may be present in only one of the rings, orin two or more rings. Examples of heteroaryl groups include, but are notlimited to, benzothiazyl, benzoxazyl, quinazolinyl, quinolinyl,isoquinolinyl, quinoxalinyl, pyridyl, pyrrolyl, oxazolyl, indolyl,thienyl, and the like. The term “heterocycle” encompasses heteroarylfused to a non-aromatic ring system.

The term “heteroatom” used herein refers to, for example, O (oxygen), S(sulfur) and N (nitrogen).

The term “heteroatom group” used herein refers to a radical containing a“heteroatom” optionally substituted with a substituent. The “heteroatomgroup” is covalently bonded to the parent molecule through the“heteroatom.” Examples of a “heteroatom group” includes, but is notlimited to, O (oxygen), S (sulfur), S(O), S(O)₂, NH and N (nitrogen)substituted with a group selected from, but are not limited to,(C₁-C₆)alkyl, aryl, heteroaryl, (C₁-C₆)alkylsulfonyl, arylsulfonyl,(C₁-C₆)alkylC(O)—, arylC(O)—, hydroxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl,heterocycle, (C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylaminocarbonyl, andarylaminocarbonyl. When the “heteroatom group” is incorporated as a partof a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system,each “heteroatom” within the “heteroatom group” is covalently bondedtwice as part of the ring system. For example, when O (oxygen) isincorporated in a ring system, the oxygen is covalently bonded twice toprovide an ether type linkage, this type of ring system includes, but isnot limited to, morpholinyl and the like. In another example, when N(nitrogen) substituted with (C₁-C₆)alkyl is incorporated in a ringsystem, the nitrogen is covalently bonded twice to provide an amine typelinkage, this type of ring system includes, but is not limited to,N-methylpiperazinyl, N-ethylpiperazinyl, N-propylpiperazinyl,N-2-propylpiperazinyl, N-butylpiperazinyl, N-2-butylpiperazinyl,N-pentylpiperazinyl, N-hexylpiperazinyl, and the like. In someembodiments, a “heteroatom group” can be a “heteroatom.” In otherembodiments, a “heteroatom group” is a “heteroatom” with a substituent,for example the substituent can be another heteroatom or a group asdisclosed herein.

The term “amino” used herein refers to a nitrogen radical substitutedwith hydrogen, alkyl, aryl, or combinations thereof. Examples of aminogroups include, but are not limited to, —NHMethyl, —NH₂, —NMethyl₂,—NPhenylMethyl, —NHPhenyl, —NEthylMethyl, and the like. An “alkylamino”refers to a nitrogen radical substituted with at least one alkyl group.Examples of alkylamino groups include, but are not limited to,—NHMethyl, —NMethyl₂, —NPropylMethyl, —NHButyl, —NEthylMethyl,—NPhenylMethyl, and the like. An “arylamino” refers to a nitrogenradical substituted with at least one aryl group. Examples of alkylaminogroups include, but are not limited to, —NPhenylMethyl, —NHPhenyl, andthe like.

The term “alkylaminocarbonyl” used herein refers to an alkylaminoradical covalently bonded to the parent molecule through the carbon of a“carbonyl” group. Examples of alkylaminocarbonyl groups include, but arenot limited to, —C(O)NHMethyl, —C(O)NMethyl₂, —C(O)NPropylMethyl,—C(O)NHButyl, —C(O)NEthylMethyl, —C(O)NPhenylMethyl, and the like.

The term “arylaminocarbonyl” used herein refers to an alkylamino radicalcovalently bonded to the parent molecule through the carbon of a“carbonyl” group. Examples of arylaminocarbonyl groups include, but arenot limited to, —C(O)NPhenylMethyl, —C(O)NHPhenyl, and the like.

The term “arylalkyl” used herein refers to one or more aryl groupsappended to an alkyl radical. Examples of arylalkyl groups include, butare not limited to, benzyl, phenethyl, phenpropyl, phenbutyl, and thelike.

The term “heteroarylalkyl” used herein refers to one or more heteroarylgroups appended to an alkyl radical. Examples of heteroarylalkylinclude, but are not limited to, pyridylmethyl, furanylmethyl,thiopheneylethyl, and the like.

The term “aryloxy” used herein refers to an aryl radical covalentlybonded to the parent molecule through an —O— linkage.

The term “alkylthio” used herein refers to straight or branched chainalkyl radical covalently bonded to the parent molecule through an —S—linkage. Examples of alkylthio groups include, but are not limited to,methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl,cyclopropylsulfanyl, butylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,t-butylsulfanyl, cyclobutylsulfanyl and the like.

The term “alkylsulfonyl” used herein refers to straight or branchedchain alkyl radical covalently bonded to the parent molecule through an—S— linkage where the sulfur is substituted with two oxygen atoms.Examples of alkylsulfonyl groups include, but are not limited to,methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,cyclopropylsulfonyl, butylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,t-butylsulfonyl, cyclobutylsulfonyl and the like.

The term “arylsulfonyl” used herein refers to optionally substitutedaryl radical covalently bonded to the parent molecule through an —S—linkage where the sulfur is substituted with two oxygen atoms. Examplesof optionally substituted arylsulfonyl groups include, but are notlimited to, phenylsulfonyl, trifluoromethylphenylsulfonyl,methoxyphenylsulfonyl, methylphenylsulfonyl, cyanophenylsulfonyl,fluorophenylsulfonyl, chlorophenylsulfonyl, bromophenylsulfonyl,biphenylsulfonyl, naphthalenylsulfonyl, phenanthrenylsulfonyl,anthracenylsulfonyl, tetralinylsulfonyl, fluorenylsulfonyl,indenylsulfonyl, and indanylsulfonyl propyl, isopropylsulfonyl,cyclopropylsulfonyl, butylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,t-butylsulfonyl, cyclobutylsulfonyl and the like.

The term “carbonyl” used herein refers to C═O (i.e. carbon double bondedto oxygen).

The term “oxo” used herein refers to ═O (i.e. double bond to oxygen).For example, cyclohexane substituted with “oxo” is cyclohexanone.

The term “alkanoyl” used herein refers to a “carbonyl” substituted withan “alkyl” group, the “alkanoyl” group is covalently bonded to theparent molecule through the carbon of the “carbonyl” group. Examples ofalkanoyl groups include, but are not limited to, methanoyl, ethanoyl,propanoyl, and the like. Methanoyl is commonly known as acetyl.

The term, “heterocyclealkanoyl” used herein refers to a “alkanoyl”substituted with an “heterocycle” group, the “heterocycle” group iscovalently bonded to the parent molecule through the carbonyl of the“alkanoyl” group. Examples of heterocyclealkanoyl groups include, butare not limited to, 2-(piperidin-1-yl)acetyl, 2-(morpholin-4-yl)acetyl,2-(piperazin-1-yl)acetyl, 2-(4-methylpiperazin-1-yl)acetyl,3-(piperidin-1-yl)propanoyl, 3-(morpholin-4-yl)propanoyl,3-(piperazin-1-yl)propanoyl, 3-(4-methylpiperazin-1-yl)propanoyl,3-(2,6-dimethylpiperidin-1-yl)propanoyl,3-(3,5-dimethylmorpholin-4-yl)propanoyl, 3-(pyrrolidin-1-yl)propanoyl,2-(pyrrolidin-1-yl)acetyl, 2-(azetidin-1-yl)acetyl,3-(azetidin-1-yl)propanoyl, ethanoyl, propanoyl, and the like.

As used herein, a radical indicates species with a single, unpairedelectron such that the species containing the radical can be covalentlybonded to another species. Hence, in this context, a radical is notnecessarily a free radical. Rather, a radical indicates a specificportion of a larger molecule. The term “radical” can be usedinterchangeably with the term “group.”

As used herein, a substituted group is derived from the unsubstitutedparent structure in which there has been an exchange of one or morehydrogen atoms for another atom or group.

Asymmetric carbon atoms may be present in the compounds described. Allsuch isomers, including diastereomers and enantiomers, as well as themixtures thereof are intended to be included in the scope of the recitedcompound. In certain cases, compounds can exist in tautomeric forms. Alltautomeric forms are intended to be included in the scope Likewise, whencompounds contain an alkenyl or alkenylene group, there exists thepossibility of cis- and trans-isomeric forms of the compounds. Both cis-and trans-isomers, as well as the mixtures of cis- and trans-isomers,are contemplated. Thus, reference herein to a compound includes all ofthe aforementioned isomeric forms unless the context clearly dictatesotherwise.

Various forms are included in the embodiments, including polymorphs,solvates, hydrates, conformers, salts, and prodrug derivatives. Apolymorph is a composition having the same chemical formula, but adifferent structure. A solvate is a composition formed by solvation (thecombination of solvent molecules with molecules or ions of the solute).A hydrate is a compound formed by an incorporation of water. A conformeris a structure that is a conformational isomer. Conformational isomerismis the phenomenon of molecules with the same structural formula butdifferent conformations (conformers) of atoms about a rotating bond.Salts of compounds can be prepared by methods known to those skilled inthe art. For example, salts of compounds can be prepared by reacting theappropriate base or acid with a stoichiometric equivalent of thecompound.

The term “pro-drug ester” refers to derivatives of the compoundsdisclosed herein formed by the addition of any of several ester-forminggroups that are hydrolyzed under physiological conditions. Examples ofpro-drug ester groups include, but are not limited to fatty acid esters,pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl,as well as other such groups known in the art, including a(5-R-2-oxo-1,3-dioxolen-4-yl)methyl group. Other examples of pro-drugester groups can be found in, for example, T. Higuchi and V. Stella, in“Pro-drugs as Novel Delivery Systems”, Vol. 14, A.C.S. Symposium Series,American Chemical Society (1975); and “Bioreversible Carriers in DrugDesign: Theory and Application”, edited by E. B. Roche, Pergamon Press:New York, 14-21 (1987) (providing examples of esters useful as prodrugsfor compounds containing carboxyl groups). Each of the above-mentionedreferences is herein incorporated by reference in their entirety.

Where a dashed line (----) appears in a structure, the dashed linerepresents a bond that is optionally present (in accordance with therules of valency), indicating, together with the single bond to which itis adjacent, either a single or double bond. A dashed line encirclingthe inside of a ring indicates that the ring is optionally aromatic orhetero aromatic.

The term “animal” as used herein includes birds, reptiles, and mammals(e.g. domesticated mammals and humans).

The terms “individual,” “host,” “subject,” and “patient” are usedinterchangeably herein, and refer to a mammal, including, but notlimited to, murines, simians, humans, mammalian farm animals, mammaliansport animals, and mammalian pets.

The term “selectively inhibiting” as used herein means that a compoundinhibits the activity of MAO-B to a greater extent than it inhibits theactivity of MAO-A (in vitro or in vivo). In one embodiment of theinvention, the compound of formula I inhibits the activity of MAO-B twotimes more than it inhibits the activity of MAO-A. In another embodimentof the invention, the compound of formula I inhibits the activity ofMAO-B five times more than it inhibits the activity of MAO-A. In anotherembodiment of the invention, the compound of formula I inhibits theactivity of MAO-B ten times more than it inhibits the activity of MAO-A.In another embodiment of the invention, the compound of formula Iinhibits the activity of MAO-B one hundred times more than it inhibitsthe activity of MAO-A.

The term “psychiatric disorder” as used herein includes psychoticdisorders, neurological disorders and neurotic disorders. The termincludes schizophrenia, age-associated memory impairment (AAMI); mildcognitive impairment (MCI), delirium (acute confusional state);depression, dementia (sometimes further classified as Alzheimer's ornon-Alzheimer's type dementia); Alzheimer's disease; Parkinson'sdisease; Huntington's disease (chorea); mental retardation; (e.g.,Rubenstein-Taybi and Downs Syndrome); cerebrovascular disease (e.g.,vascular dementia, post-cardiac surgery); affective disorders; psychoticdisorders; autism (Kanner's Syndrome); neurotic disorders; attentiondeficit disorder (ADD); subdural hematoma; normal-pressurehydrocephalus; brain tumor; head trauma (postconcussional disorder) orbrain trauma.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, stereoisomeric,or regioisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine MAO-B inhibiting activity usingthe standard tests described herein, or using other similar tests whichare well known in the art.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

For example, (C₁-C₆)alkyl includes, but is not limited to, methyl,ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl,hexyl, and the like; (C₂-C₆)alkenyl includes, but is not limited to,vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl, and the like; (C₂-C₆)alkynyl includes,but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like;(C₃-C₈)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like; (C₃-C₈)cycloalkyl(C₁-C₆)alkyl includes, but isnot limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, and the like; (C₁-C₆)alkoxyincludes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy,butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;(C₁-C₆)alkyl optionally substituted with one or more cyano includes, butis not limited to, 2-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl,4-cyanobutyl, and the like; (C₁-C₆)alkylC(O)-includes, but is notlimited to, acetyl, propanoyl butanoyl, and the like; (C₁-C₆)alkyloptionally substituted with one or more halo includes, but is notlimited to, iodomethyl, bromomethyl, chloromethyl, fluoromethyl,trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, and the like; (C₁-C₆)alkyl optionally substituted withone or more hydroxy includes, but is not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2,4-hydroxybutyl, and the like;(C₁-C₆)alkylOC(O)— includes, but is not limited to, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, or hexyloxycarbonyl; (C₁-C₆)alkylC(O)O— includes, butis not limited to, acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy,pentanoyloxy, or hexanoyloxy; (C₁-C₆)alkoxy(C₂-C₆)alkyl includes, but isnot limited to, 2-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl,3-ethoxypropyl, 4,4-dimethoxybutyl; (C₁-C₆)alkylOC(O)(C₁-C₆)alkylincludes, but is not limited to, methoxycarbonylmethyl,ethoxycarbonylmethyl, methoxycarbonylethyl, or ethoxycarbonylethyl; arylincludes, but is not limited to, phenyl, indenyl, or naphthyl; andheteroaryl includes, but is not limited to, furyl, imidazolyl,triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl,pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide),thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or itsN-oxide) or quinolyl (or its N-oxide).

Processes for preparing compounds of formula I are provided as furtherembodiments of the invention and are illustrated by the followingprocedures in which the meanings of the generic radicals are as givenabove unless otherwise qualified.

Compounds of formula I can be prepared using the general syntheticschemes illustrated below.

The thienyl carboxylic acid can be converted to an intermediate acidchloride followed by coupling with an appropriate amine to provide thedesired product. The thienyl carboxylic acid can be treated with anappropriate chlorinating agent, with or without solvent, to provide anintermediate acid chloride which can be isolated or treated directly toprovide the desired product. The thienyl carboxylic acid can beconverted to an acid chloride using a chlorinating agent in the presenceof solvent or neat. For example, the chlorinating agent can be selectedfrom oxalyl chloride, thionyl chloride, phosphorus trichloride,phosphorus oxychloride, phosgene and phosgene equivalents, and the like.The solvent can be selected from methylene chloride, chloroform,benzene, toluene and the like. In a representative example, oxalylchloride in the presence of catalytic DMF can convert the thienylcarboxylic acid to an acid chloride with toluene as the solvent.

The intermediate acid chloride can then be reacted with an amine in anappropriate solvent optionally in the presence of a base to provide thedesired product. The solvent can be selected from methylene chloride,chloroform, benzene, toluene, THF, diethyl ether, dioxane, and the like.The base can be selected from triethylamine, diisopropylethyl amine,DBU, DBN, DMAP, pyridine, and the like and combinations thereof. In arepresentative example, the acid chloride can react with the appropriateamine in the presence of THF and triethylamine as a base to provide thedesired product.

The amide can be condensed with ethyl trifluoroacetate in the presenceof solvent and a base to provide a β-diketone. The solvent can beselected from methylene chloride, DMF, NMP, toluene and the like andcombinations thereof. The base can be selected from sodium ethoxide,sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassiummethoxide, potassium tert-butoxide, sodium hydride, potassium hydride,and the like. In a representative example, the amide can react withethyl trifluoroacetate in the presence of toluene and sodium ethoxide toprovide the desired β-diketone.

The β-diketone can be converted to the isoxazole by reacting withhydroxylamine hydrochloride in an appropriate solvent, optionally, anadditional step of refluxing with trifluoroacetic acid may beadvantageous to complete the conversion. In a representative example,the β-diketone can react with hydroxylamine hydrochloride in thepresence of acetic acid followed by reacting in the presence oftrifluoroacetic acid at reflux to provide the desired isoxazole. In someembodiments a mixture of regioisomeric isoxazoles may form.

Alternatively, the β-diketone can be substituted at the α-position by analkylation then converted to the isoxazole. The β-diketone can bereacted with an alkylating agent in an appropriate solvent and base toprovide an α-substituted β-diketone. The alkylating agent can beselected from an optionally substituted alkylhalide, an optionallysubstituted alkylsulfonate and the like. The solvent can be selectedfrom DMF, NMP, THF, dioxane, and the like and combinations thereof. Thebase can be selected from sodium ethoxide, sodium methoxide, sodiumtert-butoxide, potassium ethoxide, potassium methoxide, potassiumtert-butoxide, sodium hydride, potassium hydride, and the like. In arepresentative example, the β-diketone can react with an alkylhalide inDMF with sodium hydride as the base.

The α-substituted β-diketone can be converted to the isoxazole byreacting with hydroxylamine hydrochloride in an appropriate solvent. Ina representative example, the α-substituted β-diketone can react withhydroxylamine hydrochloride in the presence of acetic acid. In someembodiments a mixture of regioisomeric isoxazoles may form.

The thienyl carboxylic acid can be converted to an thienyl carboxylicester by esterfication. For example the thienyl carboxylic acid can beconverted to a thienyl carboxylic ester by treating the thienylcarboxylic acid with acid in the presence of an alcoholic solvent andheating. The acid can be hydrochloric acid, sulfuric acid and the like.The solvent can be methyl alcohol, ethyl alcohol, and the like. In arepresentative example, the thienyl carboxylic acid can react with ethylalcohol at reflux in the presence of sulfuric acid to provide thethienyl carboxylic ester. The thienyl carboxylic ester can be condensedwith ethyl trifluoroacetate in the presence of solvent and a base toprovide a β-diketone. The solvent can be selected from methylenechloride, DMF, NMP, toluene and the like and combinations thereof. Thebase can be selected from sodium ethoxide, sodium methoxide, sodiumtert-butoxide, potassium ethoxide, potassium methoxide, potassiumtert-butoxide, sodium hydride, potassium hydride, and the like. In arepresentative example, the ester can react with ethyl trifluoroacetatein the presence of toluene and sodium ethoxide to provide the desiredβ-diketone ester.

The β-diketone ester can be substituted at the α-position by analkylation then converted to the isoxazole. The β-diketone ester can bereacted with an alkylating agent in an appropriate solvent and base toprovide an α-substituted β-diketone. The alkylating agent can beselected from an optionally substituted alkylhalide, an optionallysubstituted alkylsulfonate and the like. The solvent can be selectedfrom DMF, NMP, THF, dioxane, and the like and combinations thereof. Thebase can be selected from sodium ethoxide, sodium methoxide, sodiumtert-butoxide, potassium ethoxide, potassium methoxide, potassiumtert-butoxide, sodium hydride, potassium hydride, and the like. In arepresentative example, the β-diketone ester can react with analkylhalide in DMF with sodium hydride as the base at around 60° C.

The α-substituted β-diketone ester can be converted to the isoxazole byreacting with hydroxylamine hydrochloride in an appropriate solvent. Ina representative example, the α-substituted β-diketone ester can reactwith hydroxylamine hydrochloride in the presence of acetic acid toprovide the α-substituted isoxazole ester. The α-substituted isoxazoleester can be converted to the α-substituted isoxazole carboxylic acid byacid or base catalyzed hydrolysis. The base catalyzed hydrolysis can beaccomplished treating the α-substituted isoxazole ester with a base inan appropriate solvent in the presence of water. The base can beselected from sodium hydroxide, potassium hydroxide, lithium hydroxide,and the like. The solvent can be selected from, ethyl alcohol, methylalcohol, THF, dioxane, DMF, NMP, and the like and combinations thereof.In a representative example, the ester in THF can be hydrolyzed byreacting with lithium hydroxide in the presence of water to provide anα-substituted isoxazole carboxylic acid.

The α-substituted isoxazole carboxylic acid can be converted to anintermediate acid chloride followed by coupling with an appropriateamine to provide the desired product. The α-substituted isoxazolecarboxylic acid can be treated with an appropriate chlorinating agent,with or without solvent, to provide an intermediate acid chloride whichcan be isolated or treated directly to provide the desired product. Theα-substituted isoxazole carboxylic acid can be converted to an acidchloride using a chlorinating agent in the presence of solvent or neat.For example, the chlorinating agent can be selected from oxalylchloride, thionyl chloride, phosphorus trichloride, phosphorusoxychloride, phosgene and phosgene equivalents, and the like. Thesolvent can be selected from methylene chloride, chloroform, benzene,toluene and the like. In a representative example, oxalyl chloride inthe presence of catalytic DMF can convert the α-substituted isoxazolecarboxylic acid to an acid chloride with toluene as the solvent. Theintermediate acid chloride can then be reacted with an amine in anappropriate solvent optionally in the presence of a base to provide thedesired product. The solvent can be selected from methylene chloride,chloroform, benzene, toluene, THF, diethyl ether, dioxane, and the like.The base can be selected from triethylamine, diisopropylethyl amine,DBU, DBN, DMAP, pyridine, and the like and combinations thereof. In arepresentative example, the acid chloride can react with the appropriateamine in the presence of THF and triethylamine as a base to provide thedesired product.

Alternatively, the α-substituted isoxazole carboxylic acid can beconverted to the desired product using a coupling reaction. Theα-substituted isoxazole carboxylic acid can be reacted with a couplingagent in the presence of a catalyst and the appropriate amine in thepresence of a solvent to provide the desired product. The reaction canbe optionally run in the presence of a base. The coupling agent can beselected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide(DIC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride(EDC),O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), (Benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP), Bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrOP), and the like. The catalyst can be selectedfrom DMAP, 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole(HOAt) and the like. The solvent can be selected from methylenechloride, chloroform, DMF, NMP, THF, EtOAc, pyridine and the like. Thebase can be selected from triethylamine, diisopropylethylamine and thelike. In a representative example, the α-substituted isoxazolecarboxylic acid can react with the appropriate amine in the presence ofmethylene chloride using EDC as the coupling agent and DMAP as thecatalyst.

The thienyl carboxylic ester can be condensed with ethyl difluoroacetatein the presence of solvent and a base to provide a β-diketone. Thesolvent can be selected from methylene chloride, DMF, NMP, toluene andthe like and combinations thereof. The base can be selected from sodiumethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide,potassium methoxide, potassium tert-butoxide, sodium hydride, potassiumhydride, and the like. In a representative example, the ester can reactwith ethyl difluoroacetate in the presence of toluene and sodiumethoxide to provide the desired (β-diketoneester.

The β-diketone ester can be substituted at the α-position by analkylation then converted to the isoxazole. The β-diketone ester can bereacted with an alkylating agent in an appropriate solvent and base toprovide an α-substituted β-diketone. The alkylating agent can beselected from an optionally substituted alkylhalide, an optionallysubstituted alkylsulfonate and the like. The solvent can be selectedfrom DMF, NMP, THF, dioxane, and the like and combinations thereof. Thebase can be selected from sodium ethoxide, sodium methoxide, sodiumtert-butoxide, potassium ethoxide, potassium methoxide, potassiumtert-butoxide, sodium hydride, potassium hydride, and the like. In arepresentative example, the β-diketone ester can react with analkylhalide in DMF with sodium hydride as the base at around 60° C.

The α-substituted β-diketone ester can be converted to the isoxazole byreacting with hydroxylamine hydrochloride in an appropriate solvent. Ina representative example, the α-substituted β-diketone ester can reactwith hydroxylamine hydrochloride in the presence of acetic acid toprovide the α-substituted isoxazole ester. In some embodiments a mixtureof regioisomeric isoxazoles may form. The regioisomeric isoxazoles maybe separated and individually taken through the remaining steps or takenthrough the remaining steps as the mixture.

The α-substituted isoxazole ester can be converted to the α-substitutedisoxazole carboxylic acid by acid or base catalyzed hydrolysis. The basecatalyzed hydrolysis can be accomplished treating the α-substitutedisoxazole ester with a base in an appropriate solvent in the presence ofwater. The base can be selected from sodium hydroxide, potassiumhydroxide, lithium hydroxide, and the like. The solvent can be selectedfrom, ethyl alcohol, methyl alcohol, THF, dioxane, DMF, NMP, and thelike and combinations thereof. In a representative example, the ester inTHF can be hydrolyzed by reacting with lithium hydroxide in the presenceof water to provide an α-substituted isoxazole carboxylic acid.

The α-substituted isoxazole carboxylic acid can be converted to anintermediate acid chloride followed by coupling with an appropriateamine to provide the desired product. The α-substituted isoxazolecarboxylic acid can be treated with an appropriate chlorinating agent,with or without solvent, to provide an intermediate acid chloride whichcan be isolated or treated directly to provide the desired product. Thecc substituted isoxazole carboxylic acid can be converted to an acidchloride using a chlorinating agent in the presence of solvent or neat.For example, the chlorinating agent can be selected from oxalylchloride, thionyl chloride, phosphorus trichloride, phosphorusoxychloride, phosgene and phosgene equivalents, and the like. Thesolvent can be selected from methylene chloride, chloroform, benzene,toluene and the like. In a representative example, oxalyl chloride inthe presence of catalytic DMF can convert the α-substituted isoxazolecarboxylic acid to an acid chloride with toluene as the solvent. Theintermediate acid chloride can then be reacted with an amine in anappropriate solvent optionally in the presence of a base to provide thedesired product. The solvent can be selected from methylene chloride,chloroform, benzene, toluene, THF, diethyl ether, dioxane, and the like.The base can be selected from triethylamine, diisopropylethyl amine,DBU, DBN, DMAP, pyridine, and the like and combinations thereof. In arepresentative example, the acid chloride can react with the appropriateamine in the presence of THF and triethylamine as a base to provide thedesired product.

The thienyl β-diketone can be converted to the thienyl isoxazole byreacting with hydroxylamine hydrochloride in an appropriate solvent,optionally, an additional step of refluxing with trifluoroacetic acidmay be advantageous to complete the conversion. In a representativeexample, the β-diketone can react with hydroxylamine hydrochloride inthe presence of acetic acid followed by reacting in the presence oftrifluoroacetic acid at reflux to provide the desired thienyl isoxazole.

The thienyl isoxazole can undergo a Friedel-Crafts acylation reactionwith an acid chloride and a Lewis acid in an appropriate solvent. TheLewis acid can selected from AlCl₃, TiCl₄, FeCl₃ and the like. Thesolvent can be selected from methylene chloride, nitrobenzene carbondisulfide and the like. In a representative example, the thienylisoxazole can react in methylene chloride with an acid chloride in thepresence of FeCl₃ under reflux to provide the desired product.

The thienyl β-diketone can be substituted at the α-position by analkylation then converted to the isoxazole. The thienyl β-diketone canbe reacted with an alkylating agent in an appropriate solvent and baseto provide an α-substituted thienyl β-diketone. The alkylating agent canbe selected from an optionally substituted alkylhalide, an optionallysubstituted alkylsulfonate and the like. The solvent can be selectedfrom DMF, NMP, THF, dioxane, and the like and combinations thereof. Thebase can be selected from sodium ethoxide, sodium methoxide, sodiumtert-butoxide, potassium ethoxide, potassium methoxide, potassiumtert-butoxide, sodium hydride, potassium hydride, and the like. In arepresentative example, the thienyl β-diketone ester can react with analkylhalide in DMF with sodium hydride as the base at about 60° C.

The α-substituted thienyl β-diketone can be converted to the isoxazoleby reacting with hydroxylamine hydrochloride in an appropriate solvent.In a representative example, the α-substituted thienyl β-diketone canreact with hydroxylamine hydrochloride in the presence of acetic acid toprovide the α-substituted thienyl isoxazole.

The α-substituted thienyl isoxazole can undergo a Friedel-Craftsacylation reaction with an acid chloride and a Lewis acid in anappropriate solvent. The Lewis acid can selected from AlCl₃, TiCl₄,FeCl₃ and the like. The solvent can be selected from methylene chloride,nitrobenzene carbon disulfide and the like. In a representative example,the cc substituted thienyl isoxazole can react in methylene chloridewith an acid chloride in the presence of FeCl₃ under reflux to providethe desired α-substituted thienyl isoxazole ketone product.

4-Acetylbenzoic acid can be converted to 4-acetylbenzoic ester byesterication. For example the 4-acetylbenzoic acid can be converted to4-acetylbenzoic ester by treating 4-acetylbenzoic acid with acid in thepresence of an alcoholic solvent and heating. The acid can behydrochloric acid, sulfuric acid and the like. The solvent can be methylalcohol, ethyl alcohol, and the like. In a representative example, the4-acetylbenzoic acid can react with ethyl alcohol at reflux in thepresence of sulfuric acid to provide ethyl 4-acetylbenzoate.

The ethyl 4-acetylbenzoate can be condensed with a β-ketoester in thepresence of solvent and a base to provide a β-diketone. The solvent canbe selected from methylene chloride, DMF, NMP, toluene and the like andcombinations thereof. The base can be selected from sodium ethoxide,sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassiummethoxide, potassium tert-butoxide, sodium hydride, potassium hydride,and the like. In a representative example, the amide can react withethyl trifluoroacetate in the presence of toluene and sodium ethoxide toprovide the desired β-diketone ester.

The β-diketone ester can be substituted at the α-position by analkylation then converted to the isoxazole. The β-diketone ester can bereacted with an alkylating agent in an appropriate solvent and base toprovide an α-substituted β-diketone. The alkylating agent can beselected from an optionally substituted alkylhalide, an optionallysubstituted alkylsulfonate and the like. The solvent can be selectedfrom DMF, NMP, THF, dioxane, and the like and combinations thereof. Thebase can be selected from sodium ethoxide, sodium methoxide, sodiumtert-butoxide, potassium ethoxide, potassium methoxide, potassiumtert-butoxide, sodium hydride, potassium hydride, and the like.

If no substitution at the α-position is required, the β-diketone can beconverted directly to the isoxazole by reacting with hydroxylaminehydrochloride in an appropriate solvent. Optionally, an additional stepof refluxing with trifluoroacetic acid may be advantageous to completethe conversion. In a representative example, the β-diketone can reactwith hydroxylamine hydrochloride in the presence of acetic acid followedby reacting in the presence of trifluoroacetic acid at reflux to providethe desired isoxazole benzoic ester. In some embodiments a mixture ofregioisomeric isoxazole benzoic esters may form.

The isoxazole benzoic ester can be converted to the isoxazole benzoicacid by acid or base catalyzed hydrolysis. The base catalyzed hydrolysiscan be accomplished treating the isoxazole benzoic ester with a base inan appropriate solvent in the presence of water. The base can beselected from sodium hydroxide, potassium hydroxide, lithium hydroxide,and the like. The solvent can be selected from, ethyl alcohol, methylalcohol, THF, dioxane, DMF, NMP, and the like and combinations thereof.In a representative example, the isoxazole benzoic ester in THF can behydrolyzed by reacting with lithium hydroxide in the presence of waterto provide an isoxazole benzoic acid.

The isoxazole benzoic acid can be converted to an intermediate isoxazolebenzoic N,O-dimethylamide (i.e. Weinreb amide) followed by anorganometallic reaction to provide an isoxazole ketone.

The isoxazole benzoic acid can be can be converted to the isoxazolebenzoic N,O-dimethylamide using a coupling reaction. The isoxazolebenzoic acid can be reacted with a coupling agent in the presence of acatalyst and N,O-Dimethylhydroxylamine hydrochloride in the presence ofa solvent to provide the desired product. The reaction can be optionallyrun in the presence of a base. The coupling agent can be selected fromdicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC),O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), (Benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP), Bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrOP), and the like. The catalyst can be selectedfrom DMAP, 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole(HOAt) and the like. The solvent can be selected from methylenechloride, chloroform, DMF, NMP, THF, EtOAc, pyridine and the like. Thebase can be selected from triethylamine, diisopropylethylamine and thelike. In a representative example, the isoxazole benzoic acid can reactwith N,O-Dimethylhydroxylamine hydrochloride in the presence ofmethylene chloride using DCC as the coupling agent and DMAP as thecatalyst to provide the isoxazole benzoic N,O-dimethylamide.

The isoxazole benzoic N,O-dimethylamide can react with an organometallicreagent in an appropriate solvent to provide a isoxazole phenylketone.The organometetallic reagent can be a Grignard reagent, alkyl zinc andthe like. The solvent can be THF, dioxane, diethyl ether and the like.In a representative example, the isoxazole benzoic N,O-dimethylamide canreact with a Grignard reagent in THF to provide an isoxazolephenylketone.

The β-diketone benzoic ester can be substituted at the α-position by analkylation then converted to the isoxazole. The β-diketone benzoic estercan be reacted with an alkylating agent in an appropriate solvent andbase to provide an α-substituted β-diketone benzoic ester. Thealkylating agent can be selected from an optionally substitutedalkylhalide, an optionally substituted alkylsulfonate and the like. Thesolvent can be selected from DMF, NMP, THF, dioxane, and the like andcombinations thereof. The base can be selected from sodium ethoxide,sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassiummethoxide, potassium tert-butoxide, sodium hydride, potassium hydride,and the like.

The α-substituted β-diketone benzoic ester can be converted to theα-substituted isoxazole benzoic ester by reacting with hydroxylaminehydrochloride in an appropriate solvent. In a representative example,the α-substituted β-diketone ester can react with hydroxylaminehydrochloride in the presence of acetic acid to provide the substitutedisoxazole benzoic ester. In some embodiments a mixture of regioisomericisoxazoles may form.

The substituted isoxazole benzoic ester can be converted to thesubstituted isoxazole benzoic acid by acid or base catalyzed hydrolysis.The base catalyzed hydrolysis can be accomplished treating thesubstituted isoxazole benzoic ester with a base in an appropriatesolvent in the presence of water. The base can be selected from sodiumhydroxide, potassium hydroxide, lithium hydroxide, and the like. Thesolvent can be selected from, ethyl alcohol, methyl alcohol, THF,dioxane, DMF, NMP, and the like and combinations thereof. In arepresentative example, the ester in THF can be hydrolyzed by reactingwith lithium hydroxide in the presence of water to provide a substitutedisoxazole benzoic acid.

The substituted isoxazole benzoic acid can be converted to anintermediate substituted isoxazole benzoic N,O-dimethylamide (i.e.Weinreb amide) followed by an organometallic reaction to provide asubstituted isoxazole ketone.

The substituted isoxazole benzoic acid can be can be converted to thesubstituted isoxazole benzoic N,O-dimethylamide using a couplingreaction. The substituted isoxazole benzoic acid can be reacted with acoupling agent in the presence of a catalyst andN,O-dimethylhydroxylamine hydrochloride in the presence of a solvent toprovide the desired product. The reaction can be optionally run in thepresence of a base. The coupling agent can be selected fromdicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC),O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), (Benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP), Bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrOP), and the like. The catalyst can be selectedfrom DMAP, 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole(HOAt) and the like. The solvent can be selected from methylenechloride, chloroform, DMF, NMP, THF, EtOAc, pyridine and the like. Thebase can be selected from triethylamine, diisopropylethylamine and thelike. In a representative example, the isoxazole benzoic acid can reactwith N,O-Dimethylhydroxylamine hydrochloride in the presence ofmethylene chloride using DCC as the coupling agent and DMAP as thecatalyst to provide the substituted isoxazole benzoic N,O-dimethylamide.

The substituted isoxazole benzoic N,O-dimethylamide can react with anorganometallic reagent in an appropriate solvent to provide a isoxazolephenylketone. The organometetallic reagent can be a Grignard reagent,dialkyl zinc and the like. The solvent can be THF, dioxane, diethylether and the like. In a representative example, the substitutedisoxazole benzoic N,O-dimethylamide can react with a Grignard reagent inTHF to provide an substituted isoxazole phenylketone.

The thienyl carboxylic acid aldehyde can be converted to an intermediatethienyl acid chloride aldehyde followed by coupling with an appropriateamine to provide the desired product amide. The thienyl carboxylic acidcan be treated with an appropriate chlorinating agent, with or withoutsolvent, to provide an intermediate acid chloride which can be isolatedor treated directly to provide the desired product. The thienylcarboxylic acid aldehyde can be converted to an acid chloride using achlorinating agent in the presence of solvent or neat. For example, thechlorinating agent can be selected from oxalyl chloride, thionylchloride, phosphorus trichloride, phosphorus oxychloride, phosgene andphosgene equivalents, and the like. The solvent can be selected frommethylene chloride, chloroform, benzene, toluene and the like. In arepresentative example, oxalyl chloride in the presence of catalytic DMFcan convert the thienyl carboxylic acid aldehyde to an thienylcarboxylic acid chloride aldehyde with toluene as the solvent.

The intermediate thienyl carboxylic acid chloride aldehyde can then bereacted with an amine in an appropriate solvent optionally in thepresence of a base to provide the desired product amide. The solvent canbe selected from methylene chloride, chloroform, benzene, toluene, THF,diethyl ether, dioxane, and the like. The base can be selected fromtriethylamine, diisopropylethyl amine, DBU, DBN, DMAP, pyridine, and thelike and combinations thereof. In a representative example, the acidchloride can react with the appropriate amine in the presence of THF andtriethylamine as a base to provide the desired product thienyl aldehydeamide.

The thienyl aldehyde amide can be converted to a thienyl nitrile amidein a two step process. The thienyl aldehyde amide can be reacted withhydroxylamine hydrochloride in an appropriate solvent in the presence ofbase followed by dehydration to provide a thienyl nitrile amide. In arepresentative example, the thienyl aldehyde amide can react withhydroxylamine hydrochloride in the presence of pyridine and ethylalcohol under reflux to provide the intermediate thienyl hydroxyimineamide. The intermediate thienyl hydroxyimine amide can be dehydrated toprovide the thienyl nitrile amide. The dehydrating reagent can be aceticanhydride and the like. In a representative example, the thienylhydroxyimine amide can react with acetic anhydride at elevatedtemperature to provide the thienyl nitrile amide. The reactiontemperature can be in the range of from about 80° C. to about 90° C.

The thienyl nitrile amide can be converted to the thienyl hydroxyamidineamide by reacting the thienyl nitrile amide with hydroxylaminehydrochloride under the appropriate conditions. The thienyl nitrileamide can be reacted with hydroxylamine hydrochloride, base, water andsolvent to provide thienyl hydroxyamidine amide. The base can be sodiumacetate, potasium acetate and the like. The solvent can be methylalcohol, ethyl alcohol and the like. In a representative example, thethienyl nitrile amide can be reacted with hydroxylamine hydrochloride inthe presence of sodium acetate, water and ethyl alcohol under reflux toprovide the thienyl hydroxyamidine amide.

The thienyl hydroxyamidine amide can be converted to the azaisoxazoleamide by reacting with trifluoroacetic anhydride in an appropriatesolvent. In a representative example, the thienyl hydroxyamidine amidecan be reacted with trifluoroacetic anhydride in the presence of tolueneat elevated temperature. The reaction temperature can be in the range offrom about 80° C. to about 90° C.

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including but not limited to hydrochloride, sulfate,nitrate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

In certain aspects a prodrug form of the agent or compound may beadministered to an individual in need thereof. A “prodrug” refers to anagent that is converted into the parent drug in vivo. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the parent drug. They may, for instance, be bioavailable by oraladministration whereas the parent is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.An example, without limitation, of a prodrug would be a compound whichis administered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in Design ofProdrugs, (ed. H. Bundgaard, Elsevier, 1985), which is herebyincorporated herein by reference in its entirety.

The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will often be in the range of fromabout 0.15 to about 100 mg/kg, e.g., from about 1 to about 75 mg/kg ofbody weight per day, such as 0.75 to about 50 mg per kilogram bodyweight of the recipient per day, preferably in the range of 1 to 90mg/kg/day, most preferably in the range of 1 to 60 mg/kg/day.

The compound is conveniently administered in unit dosage form; forexample, containing 1 to 1000 mg, conveniently 10 to 750 mg, mostconveniently, 5 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about30 μM. This may be achieved, for example, by the intravenous injectionof a 0.05 to 5% solution of the active ingredient, optionally in saline,or orally administered as a bolus containing about 1-100 mg of theactive ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations.

The compounds of the invention can be administered to an animal fortreatment of age-associated memory impairment, mild cognitiveimpairment, Alzheimer's disease, Parkinson's disease and relateddiseases. The compounds of the invention can be administered to ahealthy animal or an aged animal to improve cogitative function in theanimal. The compounds of the invention can be administered to an animalhaving a condition selected from schizophrenia, age-associated memoryimpairment (AAMI); mild cognitive impairment (MCI), delirium (acuteconfusional state); depression, dementia (sometimes further classifiedas Alzheimer's or non-Alzheimer's type dementia); Alzheimer's disease;Parkinson's disease; Huntington's disease (chorea); mental retardation;(e.g., Rubenstein-Taybi and Downs Syndrome); cerebrovascular disease(e.g., vascular dementia, post-cardiac surgery); affective disorders;psychotic disorders; autism (Kanner's Syndrome); neurotic disorders;attention deficit disorder (ADD); subdural hematoma; normal-pressurehydrocephalus; brain tumor; head trauma (postconcussional disorder),brain trauma (see DSM-IV, APA 1994) and the like.

The compounds of the invention can also optionally be administered incombination with one or more other therapeutic agents that are effectiveto improve cognition and/or one or more therapeutic agents that areeffective to treat schizophrenia, age-associated memory impairment(AAMI); mild cognitive impairment (MCI), delirium (acute confusionalstate); depression, dementia (sometimes further classified asAlzheimer's or non-Alzheimer's type dementia); Alzheimer's disease;Parkinson's disease; Huntington's disease (chorea); mental retardation;(e.g., Rubenstein-Taybi and Downs Syndrome); cerebrovascular disease(e.g., vascular dementia, post-cardiac surgery); affective disorders;psychotic disorders; autism (Kanner's Syndrome); neurotic disorders;attention deficit disorder (ADD); subdural hematoma; normal-pressurehydrocephalus; brain tumor; head trauma (postconcussional disorder) orbrain trauma (see DSM-IV, APA 1994).

The ability of a compound of the invention to act as an inhibitor ofMAO-B can be determined using pharmacological models which are wellknown to the art, or using the following assay.

MAO Inhibition Assay

MAO enzymatic assay was performed according to the fluorometric methoddescribed by Matsumoto and colleagues (Matsumoto, et. al., Clin.Biochem., 1985 18, 126-129). with the following modifications. Humanrecombinant MAO-A and MAO-B expressed in insect cells were used. Forboth assays, test compound and/or vehicle was preincubated with purifiedenzyme in phosphate buffer pH 7.4 for 15 minutes at 37° C. The reactionwas initiated by addition of 50 μM kynuramine. Following a 60 minuteincubation period, the reaction was terminated by the addition of 6 NNaOH. The amount of 4-hydroxyquinoline formed was determinedspectrofluorimetrically at 325 nm/465 nm. Results were converted topercent inhibition and IC₅₀'s were determined using the XLfit programfrom IDBS (ID Business Solutions Ltd., 2 Occam Court, Surrey ResearchPark, Guildford, Surrey, GU2 7QB UK). Representative compounds of theinvention were evaluated in this assay. Typically, the compounds of theinvention showed MAO-B inhibitory properties at a concentration of 10μM. Preferred compounds also demonstrated selectivity for MAO-B overMAO-A.

In many embodiments, a subject compound shows MAO-B inhibitoryproperties at a concentration of less than about 50 μM, e.g., a subjectcompound shows MAO-B inhibitory properties at a concentration of lessthan about 40 μM, less than about 25 μM, less than about 10 μM, lessthan about 1 μM, less than about 100 nM, less than about 80 nM, lessthan about 60 nM, less than about 50 nM, less than about 25 nM, lessthan about 10 nM, or less than about 1 nM, or less.

A majority of the following compounds showed MAO-B inhibitory propertiesat a concentration of 10 μM or less:

The ability of a compound to modulate cognitive behavior can beevaluated using the following assay to measure memory after contextualfear conditioning.

Contextual Memory Assay: Fear Conditioning

Contextual memory is a form of Pavlovian fear conditioning in which anaïve mouse is placed into a novel chamber (context) containing distinctvisual, olfactory and tactile cues. After a couple of minutes ofacclimation, the mouse receives a brief, mild electric shock to itsfeet. From this negative experience, the mouse will remember for monthsthat that chamber is dangerous. When placed back into the same contextat some later time after training, the mouse's natural response todanger is to “freeze,” sitting stone still for many seconds. This issimilar to what happens to humans when they experience fear. The percentof time during an observation period that the mouse spends frozenrepresents a quantitative measure (memory score) of its memory of thecontext.

Contextual conditioning has been extensively used to investigate theneural substrates mediating fear-motivated learning (Phillips, R. G.,LeDoux, J. E., Behav Neurosci, 1992, 106, 274-285; Kim, J. J., et. al.,Behav Neurosci, 1993, 107, 1093-1098; Bourtchouladze, R., et. al., LearnMem, 1998, 5, 365-374; and Bourtchouladze, R et. al., Cell, 1994, 79,59-68). Contextual conditioning has been also used to study the impactof various mutations on hippocampus-dependent memory (Bourtchouladze,R., et. al., Learn Mem, 1998, 5, 365-374; Bourtchouladze, R., et. al.,Cell, 1994, 79, 59-68.; Silva, A. J., et. al., Curr Biol, 1996, 6,1509-1518; Kogan J. L. et al., Curr Biol, 1997, 7, 1-11; Abel, T., et.al., Cell, 1997, 88, 615-626; and Giese K. P., et al., Science, 1998,279, 870-873); and strain and genetic background differences in mice(Logue, S. F., et. al., Behav Neurosci, 1997, 111, 104-113; and Nguyen,P. V., et. al., Learn Mem, 2000, 7, 170-179). Because robust memory canbe triggered with a few minutes training session, contextualconditioning has been especially useful to study biology of temporallydistinct processes of short- and long-term memory (Kim, J. J., et. al.,Behav Neurosci, 1993, 107, 1093-1098; Bourtchouladze, R., et. al., LearnMem, 1998, 5, 365-374; Bourtchouladze, R., et. al., Cell, 1994, 79,59-68; and Abel, T., et. al., Cell, 1997, 88, 615-626). As such,contextual conditioning is an excellent model to evaluate the role ofvarious novel drug-compounds in hippocampus-dependent memory.

Young-adult (10-12 weeks old) C57BL/6 male mice and Sprague Dawley malerats of 250-300 g (Taconic, N.Y.) were used. Mice were group-housed (5mice) in standard laboratory cages while rats were housed in pairs andmaintained on a 12:12 light-dark cycle. The experiments were alwaysconducted during the light phase of the cycle. With the exception oftesting times, the mice had ad lib access to food and water. Theexperiments were conducted according with the Animal Welfare assurance#A3280-01 and animals were maintained in accordance with the animalWelfare Act and Department of Health and Human Services guide.

To assess contextual memory, a modified contextual fear conditioningtask originally developed for evaluation of memory in CREB knock-outmice was used (Bourtchouladze, R., et. al., Cell, 1994, 79, 59-68). Onthe training day, the mouse was placed into the conditioning chamber(Med Associates, Inc., VA) for 2 minutes before the onset ofunconditioned stimulus (US), 0.5 mA, of 2 sec foot shock. The US wasrepeated two times with a 1 min inter-trial interval between shocks.Training was performed by automated software package (Med Associates,Inc., VA). After the last training trial, the mice were left in theconditioning chamber for another 30 sec and were then placed back intheir home cages. 24 hours after training, the mouse was placed into thesame training chamber and contextual memory was assessed by scoringfreezing behavior (‘freezing’ serves as memory score). Freezing wasdefined as the complete lack of movement in intervals of 5 seconds (Kim,J. J., et. al., Behav Neurosci, 1993, 107, 1093-1098; Phillips, R. G.,LeDoux, J. E., Behav Neurosci, 1992, 106, 274-285; Bourtchouladze, R.,et. al., Learn Mem, 1998, 5, 365-374; Bourtchouladze, R., et. al., Cell,1994, 79, 59-68; and Abel, T., et. al., Cell, 1997, 88, 615-626). Totaltesting time lasted 3 minutes. After each experimental subject, theexperimental apparatus was thoroughly cleaned with 75% ethanol, water,dried, and ventilated for a few minutes.

All experiments were designed and performed in a balanced fashion,meaning that (i) for each experimental condition (e.g. a specificdose-effect) an equal number of experimental and control mice was used;and (ii) each experimental condition was replicated 2-3 independenttimes, and replicate days were added to generate final number ofsubjects. The proceeding of each experiment was filmed. In eachexperiment, the experimenter was unaware (blind) to the treatment of thesubjects during training and testing. Data were analyzed by Student'sunpaired t test using a software package (Statview 5.0.1; SAS Institute,Inc). All values in the text and figures are expressed as mean±SEM.

Compounds were dissolved in 1% DMSO/PBS and administeredintraperitonially (I.P.) in a volume of 8 mL/kg 20 min before training.Control animals received vehicle alone (1% DMSO/PBS). For oraladministration the compounds were dissolved in 30% DMSO/70% CMC.Consequently, control animals received 30% DMSO/70% CMC. For eachtraining and drug-injecting procedure, an experimentally naïve group ofanimals were used.

The ability of a compound to modulate cognitive behavior can also beevaluated using the following Object Recognition Assay.

Object Recognition Assay

Object recognition is an ethologically relevant task for rodents, whichdoes not result from negative reinforcement (foot shock). This taskrelies on the natural curiosity of rodents to explore novel objects intheir environments more than familiar ones. Obviously, for an object tobe “familiar,” the animal must have attended to it before and rememberedthat experience. Hence, animals with better memory will attend andexplore a new object more than an object familiar to them. Duringtesting, the animal is presented with the training object and a second,novel one. Memory of the training object renders it familiar to theanimal, and it then spends more time exploring the new novel objectrather than the familiar one (Bourtchouladze, R., et. al., Proc NatlAcad Sci USA, 2003, 100, 10518-10522). Recent neuroimaging studies inhumans demonstrated that memory in object recognition depends onprefrontal cortex (PFC) (Deibert, et. al., Neurology, 1999, 52,1413-1417). Consistent with these findings, rats with the PFC lesionsshow poor working memory when they are required to discriminate betweenfamiliar and novel objects (Mitchell, J. B., Laiacona, J., Behav BrainRes, 1998, 97, 107-113). Other studies on monkeys and rodents suggestthat the hippocampus is important for novel object recognition (Teng,E., et. al., J. Neurosci, 2000, 20, 3853-3863; and Mumby, D. G., BrainRes, 2001, 127, 159-181). Hence, object recognition provides anexcellent behavioral model to evaluate drug-compound effects oncognitive task associated with function of hippocampus and cortex.

Prior to initiation of training, animals were handled for 3-5 minutesfor 5 days. Training and testing were performed identically for mice andrats with an exception of training apparatus dimensions (for mice: aPlexiglas box of L=48 cm; W=38 cm and H=20 cm; for rats: a Plexiglas boxof L=70 cm; W=60 cm and H=35 cm). The day before training, an individualanimal was placed into a training apparatus located in a dimly lit roomand allowed to habituate to the environment for 15 minutes (also seePittenger, C., et. al., Neuron, 2002, 34, 447-462; and Bourtchouladze,R., et. al., Proc Natl Acad Sci USA, 2003, 100, 10518-10522). Trainingwas initiated 24 h hours after habituation. An animal was placed backinto the training box, which contained two identical objects (e.g. asmall conus-shape object), and was allowed to explore these objects. Theobjects were placed into the central area of the box and the spatialposition of objects (left-right sides) was counterbalanced betweensubjects. Animals were trained for 15 minutes. To test for memoryretention, animals were observed for 10 minutes 24 hours after training.A rodent was presented with two objects, one of which was used duringtraining, and thus was ‘familiar’ and the other of which was novel (e.g.a small pyramid-shape object). To insure that the discrimination targetsdo not differ in smell, after each experimental subject, the apparatusand the objects were thoroughly cleaned with 90% ethanol, dried andventilated for a few minutes.

The experiments were videotaped via an overhead video camera system.Types were then reviewed by a blinded observer and the followingbehavioral parameters were determined: time of exploration of an eachobject; the total time of exploration of the objects; number ofapproaches to the objects; and time (latency) to first approach to anobject. The discrimination index—memory score—was determined asdescribed previously (Ennaceur, A., Aggleton, J. P., Behav Brain Res,1997, 88, 181-193; and Bourtchouladze, R., et. al., Proc Natl Acad SciUSA, 2003, 100, 10518-10522). This Data was analyzed by Student'sunpaired t test using a software package (Statview 5.0.1; SAS Institute,Inc).

The compounds evaluated in the MAO Inhibition Assay can be tested in theObject Recognition Assay to show improvement of cognitive function inthe subject animal.

The following Examples illustrate methods that are generally useful forpreparing compounds of the invention.

LC Protocol: Observed, 254 nm. Solvent system, acetonitrile (0.1% formicacid) and water (0.1% formic acid). Column, XTerra MS C-18 3.5 μM(2.1×50 mm), 30° C. oven temperature. Run time, 10 min. Flow rate 0.3mL/min. Substrate is dissolved in acetonitrile and diluted to equalvolume with water for injection.

Inlet Method:

Time (min) % acetonitrile (0.1% formic acid) % water (0.1% formic acid)0 10 90 5 90 10 7 90 10 7.5 10 90 10 10 90

PREPARATIVE EXAMPLES Preparative Example 1

1-[5-(Piperidine-1-carbonyl)-thiophen-2-yl]-ethanone

A solution of 5-acetylthiophene-2-carboxylic acid (34.0 g, 200 mmol) intoluene (800 mL) was treated with DMF (500 μL) followed by oxalylchloride (22.3 mL, 260 mmol) and allowed to stir 3 hr after which timethe reaction was evaporated in vacuo to afford intermediate acidchloride. The intermediate acid chloride was then dissolved in THF (500mL) and treated with a THF solution (100 mL) of triethylamine (30.7 mL,220 mmol) and piperidine (20.7 mL, 210 mmol). The reaction was allowedto stir for 3 hr then evaporated to approximately ¼ volume andpartitioned between EtOAc (150 mL) and a 1N HCl solution (100 mL). Theorganic portion was then further washed with a saturated aqeuoussolution of NaHCO₃ (100 mL) followed by a brine solution (100 mL), thendried over MgSO₄, filtered, and evaporated in vacuo to afford product asyellow colored solid which was triturated and filtered with the aid ofhexanes to afford product as a solid (43.2 g, 91%). ¹H NMR (CDCl₃)1.63-1.71 (m, 6 H), 2.57 (s, 3 H), 3.62 (br s, 4 H), 7.24 (d, J=4.0, 1H), 7.60 (d, J=4.0, 1 H). ¹³C NMR 24.7, 26.3 (br), 27.1, 44.5 (br), 48.0(br), 128.8, 131.6, 144.7, 145.5, 162.7, 190.8. LC/MS 4.92 min, [M+1]⁺238.

Preparative Example 2

5-Acetyl-thiophene-2-carboxylic acid ethyl ester

A solution of 5-acetylthiophene-2-carboxylic acid (17.0 g, 100 mmol) inethanol (500 mL) was treated with a concentrated H₂SO₄ solution (10 mL)and heated at reflux for 3 days after which time the reaction wasevaporated to approximately ¼ volume and partitioned between EtOAc (300mL) and water (100 mL). The organic portion was then further washed witha saturated aqueous solution of NaHCO₃ (2×100 mL) followed by a brinesolution (100 mL), then dried over MgSO₄, filtered, and evaporated invacuo to afford product as light brown colored solid (25.0 g, 84%). ¹HNMR (CDCl₃) 1.39 (t, J=7.0, 3 H), 2.59 (s, 3 H), 4.38 (q, J=7.3, 2 H),7.64 (d, J=4.0, 1 H), 7.76 (d, J=4.0, 1 H). ¹³C NMR 14.3, 27.1, 61.9,131.8, 133.3, 140.3, 148., 161.7, 190.9. LC/MS 5.47 min, [M+1]⁺ 199.

Preparative Example 3

4,4,4-Trifluoro-1-[5-(piperidine-1-carbonyl)-thiophen-2-yl]-butane-1,3-dione

A suspension of sodium methoxide (8.78, 162.5 mmol) in toluene (300 mL)was treated with ethyl trifluoroacetate and allowed to stir at 30° C.for 30 min after which time solid1-[5-(Piperidine-1-carbonyl)-thiophen-2-yl]-ethanone (PreparativeExample 1, 11.87 g, 50 mmol) was added portionwise. The reaction washeated at 40° C. for 3 hr and allowed to stir at room temperature for afurther 16 hr. The reaction was then cooled to 0-5° C. and filtered withthe aid of cold toluene. The filtered solids were then partitionedbetween EtOAc (300 mL) and an aqueous 5% H₂SO₄ solution (100 mL) and theorganic layer further washed with a brine solution (2×50 mL), then driedover MgSO₄, filtered, and evaporated in vacuo to afford product as lightbrown colored solid (15.26 g, 91%). An approx. 2:1 isomer mixture wasobserved in the NMR spectra of product. ¹H NMR (CDCl₃) 1.65-1.71 (m, 6H), 3.63 (br s, 4 H), 7.06 (s, 1 H), 5.38 (br s, minor enol, 1 H), 6.45(s, major isomer, 1 H), 7.25 (d, minor isomer, J=3.8, 1 H), 7.28 (d,major isomer, J=4.1, 1 H), 7.71 (d, minor isomer, J=4.1, 1 H), 7.74 (d,major isomer, J=3.8, 1 H). ¹⁹F NMR −87.3 (minor isomer), −76.2 (majorisomer). LC/MS 5.05 min, [M+1+H₂O]⁺ 352.

Preparative Example 4

4,4,4-Trifluoro-2-methyl-1-[5-(piperidine-1-carbonyl)-thiophen-2-yl]-butane-1,3-dione

A suspension of 60% sodium hydride (440 mg, 11 mmol) in DMF (15 mL) at0-5° C. was treated portionwise with4,4,4-Trifluoro-1-[5-(piperidine-1-carbonyl)-thiophen-2-yl]-butane-1,3-dione(Preparative Example 3, 3.34 g, 10 mmol) and allowed to stir until allhydrogen evolution had ceased. The reaction mixture was then treatedwith iodomethane (1.25 mL, 20 mmol) and heated at 60° C. for 16 hr. Thereaction mixture was then cooled and partitioned between EtOAc (25 mL)and an aqueous 5% H₂SO₄ solution (50 mL) and the organic layer furtherwashed with a brine solution (2×25 mL), then dried over MgSO₄, filtered,and evaporated in vacuo to afford product as light brown oil. Theresidue was chromatographed on silica gel with EtOAc/hexanes (50%) aseluant to afford product as an oil (2.70 g, 78%). An approximately 1:1mixture of isomers was observed in the NMR spectra of product. ¹H NMR(CDCl₃) 1.40 (d, isomer, J=7.0, 3 H), 1.58 (d, isomer, J=7.0, 3 H),1.65-1.71 (m, 6 H), 3.63 (br s, 4 H), 3.83 (q, isomer, J=7.0, 1 H), 4.78(q, isomer, J=6.7, 1 H), 5.06 (s, isomer, 1 H), 5.67 (s, isomer, 1 H),7.27 (d, isomer, J=4.0, 1 H), 7.29 (d, isomer, J=4.0, 1 H), 7.71 (d,isomer, J=4.0, 1 H), 7.74 (d, isomer, J=4.0, 1 H). ¹⁹F NMR −83.7(isomer), −77.6 (isomer). LC/MS 5.05 min, [M+1+H₂O]⁺ 366.

Preparative Example 5

5-(4,4,4-Trifluoro-3-oxo-butyryl)-thiophene-2-carboxylic acid ethylester

Prepared from 5-Acetyl-thiophene-2-carboxylic acid ethyl ester asdescribed in Preparative Example 3. Sodium methoxide was substitutedwith sodium ethoxide. Product was not chromatographed, but obtained as ayellow solid (11.5 g, 78%). ¹H NMR (CDCl₃) 1.41 (t, J=7.0, 3 H), 4.41(q, J=7.0, 2 H), 6.48 (s, 1 H), 7.77 (d, J=7.0, 1 H), 7.81 (d, J=4.0, 1H). ¹³C NMR 14.4, 62.3, 93.8, 117.5 (q, J=281), 132.0, 133.7, 141.5,143.7, 161.4, 174.0 (q, J=37), 181.4. ¹⁹F NMR −76.4. LC/MS 5.44 min,[M+1]⁺295, [M+1+H₂O]⁺ 313.

Preparative Example 6

5-(4,4,4-Trifluoro-2-methyl-3-oxo-butyryl)-thiophene-2-carboxylic acidethyl ester

Prepared from 5-(4,4,4-Trifluoro-3-oxo-butyryl)-thiophene-2-carboxylicacid ethyl ester as described in Preparative Example 4. Product was notchromatographed, but obtained as a brown oil (12.2 g, 113%) and used assuch. LC/MS 5.81 min, [M+1+H₂O]⁺ 327.

Preparative Example 7

4-(4,4,4-Trifluoro-3-oxo-butyryl)-benzoic acid ethyl ester

Prepared from 4-Acetyl-benzoic acid ethyl ester as described inPreparative Example 3. Sodium methoxide was substituted with sodiumethoxide. Product was not chromatographed, but obtained as an off-whitesolid (10.4 g, 90%). ¹H NMR (CDCl₃) 1.43 (t, J=7.0, 3 H), 4.43 (q,J=7.3, 2 H), 6.61 (s, 1 H), 8.00 (d, J=8.8, 2 H), 8.40 (d, J=8.4, 2 H).¹⁹F NMR −77.1. LC/MS 5.51 min, [M+1]⁺ 289, [M+1+H₂O]⁺ 307.

Preparative Example 8

4-(4,4,4-Trifluoro-2-methyl-3-oxo-butyryl)-benzoic acid ethyl ester

Prepared from 4-(4,4,4-Trifluoro-3-oxo-butyryl)-benzoic acid ethyl esteras described in Preparative Example 4. Sodium methoxide was substitutedwith sodium ethoxide. Product was chromatographed on silica gel withEtOAc/hexanes (15%) to afford a copper-colored oil (1.14 g, 38%). LC/MS5.94 min, [M+1]⁺ 303, [M+1+H₂O]⁺ 321.

Preparative Example 9

4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid ethyl ester

A solution of 4-(4,4,4-Trifluoro-3-oxo-butyryl)-benzoic acid ethyl ester(Preparative Example 7, 2.88 g, 10 mmol) in glacial acetic acid (2.5 mL)was treated with hydroxylamine hydrochloride (833 mg, 12 mmol) andheated at 80-90° C. for 16 hr, after which time the reaction was cooledand the resulting solids filtered with the aid of water to afford the5-hydroxy-4,5-dihydro-isoxazole intermediate (2.25 g, 74%). Theintermediate (2.2 g, 7.25 mmol) was then dissolved in trifluoroaceticacid (10 mL) and heated at reflux for 3 days. The reaction was thenevaporated and the residue chromatographed on silica gel withEtOAc/hexanes (20%) as eluant to afford product as a colorless solid(1.30 g, 63%). ¹H NMR (CDCl₃) 1.41 (t, J=7.5, 3 H), 4.41 (q, J=7.0, 2H), 7.06 (s, 1 H), 7.89 (d, J=8.8, 2 H), 8.15 (d, J=8.8, 2 H). ¹³C NMR14.5, 61.7, 103.8, 118.0 (q, J=270), 127.1, 130.6, 131.5, 132.8, ˜150quartet not resolved from baseline noise, 162.0, 166.0. ¹⁹F NMR −63.6.LC/MS 7.15 min, [M+1]⁺ 286.

Preparative Example 10

4-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-benzoic acid ethyl ester

A solution of 4-(4,4,4-Trifluoro-2-methyl-3-oxo-butyryl)-benzoic acidethyl ester

(927 mg, 3.07 mmol) in glacial acetic acid (10 mL) was treated withhydroxylamine hydrochloride (256 mg, 3.68 mmol) and heated at 80-90° C.for 48 hr, after which time the reaction was evaporated in vacuo. Thecrude material was then chromatographed on silica gel with EtOAc/hexanes(5%) as eluant to afford product as a colorless oil (840 mg, 91%). ¹HNMR (CDCl₃) 1.43 (t, J=7.0, 3 H), 2.29 (q, J=3 H), 4.43 (q, J=7.0, 2 H),7.72 (d, J=8.8, 2 H), 8.19 (d, J=8.3, 2 H). ¹³C NMR 7.7, 14.5, 61.6,115.0, 118.9 (q, J=271), 128.5, 130.3, 132.1, 132.3, ˜150 quartet notresolved from baseline noise, 163.0, 166.0. ¹⁹F NMR −63.2. LC/MS 7.28min, [M+1]⁺ 300.

Preparative Example 11

4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid

A solution of 4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid ethylester (Preparative Example 9, 2.25 g, 7.86 mmol) in THF (20 mL) wastreated with an aqueous solution (5 mL) of lithium hydroxide monohydrate(660 mg, 15.72 mmol) and allowed to stir for 16 hr. The reaction wasthen evaporated to a small volume and treated with a 1 N aqueoushydrochloric acid solution (25 mL) and the resulting solids filtered,washed with water and air dried to afford product as a colorless solid(1.48 g, 73%). ¹H NMR (DMSO-d6) 8.06 (s, 4 H), 8.13 (s, 1 H). ¹³C NMR106.5, 118.0 (q, J=270), 127.9, 130.8, 131.2, 132.4, ˜150 quartet notresolved from baseline noise, 133.8, 162.8, 167.3. ¹⁹F NMR −63.6. LC/MS6.04 min, [M+1]⁺ 258.

Preparative Example 12

4-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-benzoic acid

Prepared from 4-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-benzoic acidethyl ester as described in Preparative Example 11 to afford product asa colorless solid (3.7 g, 98%). ¹H NMR (DMSO-d6) 2.25 (s, 3 H), 7.81 (d,J=7.9, 2 H), 8.10 (d, J=8.2, 2 H), 13.26 (s, 1 H). ¹³C NMR 7.8, 116.9,119.3 (q, J=270), 129.3, 130.6, 131.6, 133.2, 153.6 (q, J=39), 163.6,167.4. ¹⁹F NMR −62.3. LC/MS 6.14 min, [M+1]⁺ 272.

Preparative Example 13

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidethyl ester

Prepared from crude5-(4,4,4-Trifluoro-2-methyl-3-oxo-butyryl)-thiophene-2-carboxylic acidethyl ester as described in Preparative Example 10. Crude material waschromatographed on silica gel with EtOAc/hexanes (25%) as eluant toafford product as a colorless solid (7.4 g, 66%). ¹H NMR (CDCl₃) 1.41(t, J=7.0, 3 H), 2.38 (s, 3 H), 4.43 (q, J=7.5, 2 H), 7.51 (d, J=4.0, 1H), 7.83 (d, J=4.0, 1 H). ¹³C NMR 7.9, 14.5, 61.9, 114.8, 118.7 (q,J=271), 128.4, 133.6, 134.7, 136.6, 155.4 (q, J=41), 157.9, 161.8. ¹⁹FNMR −63.2. LC/MS 7.26 min, [M+1]⁺ 306.

Preparative Example 14

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidethyl ester as described in Preparative Example 11 to afford product asa colorless solid (6.15 g, 94%). ¹H NMR (DMSO-d6) 2.33 (s, 3 H),7.64-7.66 (m, 2 H). ¹³C NMR 8.0, 116.6, 119.1 (q, J=271), 129.3, 130.7,131.8, 132.4, 142.7, 153.8 (q, J=40), 158.8, 163.6. ¹⁹F NMR −62.3. LC/MS6.02 min, [M+1]⁺ 278.

Preparative Example 15

N-Methoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3-yl)-benzamide

A solution of 4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid(Preparative Example 11, 1.024 g, 4.0 mmol) in dichloromethane (14 mL)at 0-5° C. was treated with DMF (2 mL) followed by DMAP (50 mg),hydroxylamine hydrochloride (468 mg, 4.8 mmol), triethylamine (458 μL,4.8 mmol), and DCC (990 mg, 4.8 mmol). The reaction was allowed to warmto room temperature and stirred 16 hr then evaporated in vacuo. Thecrude material was then chromatographed on silica gel with EtOAc/hexanes(40%) as eluant to afford product as a colorless solid (890 mg, 74%). ¹HNMR (CDCl₃) 3.40 (s, 3 H), 3.57 (s, 3 H), 7.06 (s, 3), 7.82 (d, J=8.3, 2H), 7.88 (d, J=8.8, 2 H). ¹³C NMR 33.7, 61.4, 103.7, 118.0 (q, J=460),127.1, 129.3, 129.4, 136.6, 159.7 (q, J=42), 162.2, 169.0. ¹⁹F NMR−64.6. LC/MS 6.01 min, [M+1]⁺ 301.

Preparative Example 16

N-Methoxy-N-methyl-4-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-benzamide

Prepared from 4-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-benzoic acidas described in Preparative Example 15. Crude material waschromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluantto afford product as a colorless solid (1.41 g, 75%). ¹H NMR (CDCl₃)2.26 (s, 3 H), 3.36 (s, 3 H), 3.55 (s, 3 H), 7.65 (d, J=7.9, 2 H), 7.80(d, J=7.9, 2 H). ¹³C NMR 7.7, 33.7, 61.4, 117.1, 117.9 (q, J=428),128.2, 129.0, 130.0, 136.1, 155 (obs q), 163.1, 169.1. ¹⁹F NMR −63.2.LC/MS 6.27 min, [M+1]⁺ 315.

Preparative Example 17

5-(Piperidine-1-carbonyl)-thiophene-2-carbaldehyde

A solution of 5-formylthiophenecarboxylic acid (9.0 g, 57.6 mmol) intoluene (100 mL) was treated with DMF (100 μL) followed by oxalylchloride (9.9 mL, 115 mmol) and stirred at room temperature for 3 hrthen evaporated in vacuo. The crude acid chloride was then dissolved inTHF (100 mL), cooled in an ice bath, and treated with a THF solution (50mL) containing triethylamine (10 mL, 72 mmol) and piperidine (6.3 mL,63.4 mmol). The reaction was placed in a 5° C. refrigerator for 16 hrand then treated with a 1N HCl solution (200 mL) and EtOAc (200 mL). Theorganic portion was further washed with a saturated aqueous solution ofNaHCO₃ (100 mL) followed by a brine solution (100 mL), then dried overMgSO₄, filtered, and evaporated in vacuo to afford product as an oil(12.87 g, 100%). ¹H NMR (CDCl₃) 1.64-1.71 (m, 6 H), 3.62 (br s, 4 H),7.31 (d, J=4.0, 1 H), 7.71 (d, J=3.5, 1 H), 9.94 (s, 1 H). ¹³C NMR 24.6,26.3 (br), 44.2 (br), 49.0 (br), 128.8, 135.4, 144.8, 146.1, 162.5,183.3. LC/MS 4.78 min, [M+1]⁺ 224.

Preparative Example 18

5-(Piperidine-1-carbonyl)-thiophene-2-carbonitrile

A solution of 5-(Piperidine-1-carbonyl)-thiophene-2-carbaldehyde(Preparative Example 17, 2.23 g, 10 mmol) in EtOH (50 mL) was treatedwith pyridine (971 μL, 12 mmol, 1.2 eq) followed by hydroxylaminehydrochloride (833 mg, 12 mmol, 1.2 eq) and heated at reflux for 2 hrthen evaporated in vacuo. The crude intermediate oxime was thendissolved in acetic anhydride and heated at 145° C. for 16 hr thenevaporated in vacuo to a small volume which was partitioned betweenEtOAc (50 mL) and water (200 mL). The organic layer was further washedwith a brine solution (50 mL), dried over MgSO₄, filtered, evaporated invacuo and the residue chromatographed on silica gel with EtOAc/hexanes(30 then 50%) as eluant to afford product as a yellow-tinted oil (1.43g, 65%). ¹H NMR (CDCl₃) 1.65-1.76 (m, 6 H), 3.64 (br s, 4 H), 7.23 (d,J=4.0, 1 H), 7.56 (d, J=4.0, 1 H). ¹³C NMR 24.5, 26.2, 44.3 (br), 48.5(br), 111.9, 113.7, 128.0, 137.0, 144.7, 161.3. LC/MS 5.09 min, [M+1]⁺221.

Preparative Example 19

4,4,4-Trifluoro-2-methyl-1-thiophen-2-yl-butane-1,3-dione

Prepared from 2-Thenoyltrifluoroacetone as described in PreparativeExample 4. Product was not chromatographed, but obtained as a brown oil(13.6 g, 115%) and used as such. LC/MS 4.99 min, [M+1+H₂O]⁺ 255.

Preparative Example 20

3-Thiophen-2-yl-5-trifluoromethyl-isoxazole

Prepared from 2-Thenoyltrifluoroacetone as described in PreparativeExample 9. Product was chromatographed on silica gel with EtOAc/hexanes(5%) as eluant to afford product as a colorless solid (2.57 g, 59%).Intermediate: LC/MS 5.23 min, [M+1+H₂O]⁺ 255. Product: ¹H NMR (CDCl₃)6.93 (s, 1 H), 7.14 (dd, J=3.5 and 4.8, 1 H), 7.47-7.52 (m, 2 H). ¹³CNMR 103.7, 118.0 (q, J=271), 128.2, 128.9, 129.1, 158.0, 159.3 (q,J=43). ¹⁹F NMR −64.7. LC/MS 6.62 min, [M+1]⁺ 220.

Preparative Example 21

4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole

Prepared from crude4,4,4-Trifluoro-2-methyl-1-thiophen-2-yl-butane-1,3-dione as describedin Preparative Example 10. Product was not chromatographed, but obtainedas a colorless solid after filtration with aid of water (3.05 g, 65%).¹H NMR (CDCl₃) 2.35 (s, 3 H), 7.16-7.19 (m, 1 H), 7.49-7.52 (m, 2 H).¹³C NMR 7.9, 114.6, 118.9 (q, J=271), 128.1, 128.6, 128.7, 154.9 (q,J=40), 158.5. ¹⁹F NMR −63.2. LC/MS 6.79 min, [M+1]⁺ 234.

Preparative Example 22

5-(4,4-Difluoro-3-oxo-butyryl)-thiophene-2-carboxylic acid ethyl ester

Prepared from 5-Acetyl-thiophene-2-carboxylic acid ethyl ester and ethyldifluoroacetate by the method described in Preparative Example 3. Sodiummethoxide was substituted with sodium ethoxide. The product was obtainedas a crude oil (5.4 g, 85%). An approx. 5:1 isomer mixture was observedin the NMR spectra of product. ¹H NMR (CDCl₃) 1.41 (t, J=7.0, 3 H), 3.63(q, J=7.0, 2 H), 5.98 (t, minor isomer, J=53.2, 1 H), 6.05 (t, majorisomer, J=54.0, 1 H), 6.45 (s, 1 H), 7.74 (d, J=4.0, 1 H), 7.80 (d,J=4.0, 1 H). ¹⁹F NMR −127.8 (minor isomer, J=53.5), −127.1 (majorisomer, J=55.5). LC/MS 5.18 min, [M+1]⁺ 277.

Preparative Example 23

5-(4,4-Difluoro-2-methyl-3-oxo-butyryl)-thiophene-2-carboxylic acidethyl ester

Prepared from 5-(4,4-Difluoro-3-oxo-butyryl)-thiophene-2-carboxylic acidethyl ester by the method described in Preparative Example 4 to affordproduct as a crude oil (5.5 g, 108%). LC/MS 5.37 min, [M+1]⁺ 291.

Preparative Example 24 and 25

5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-thiophene-2-carboxylic acidethyl ester and5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidethyl ester

Prepared from5-(4,4-Difluoro-2-methyl-3-oxo-butyryl)-thiophene-2-carboxylic acidethyl ester by the method described in Preparative Example 10. The crudematerial was chromatographed on silica gel with EtOAc/hexanes (10%) aseluant and the pure fractions isolated to afford products as colorlesssolids. High Rf material (Rf=0.40, 440 mg, 9%), low Rf material(Rf=0.24, 1.1 g, 22%), as well as an approximately 1:1 mixture ofisomers (1.5 g, 30%).

Higher Rf Product:5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-thiophene-2-carboxylic acidethyl ester: ¹H NMR (CDCl₃) 1.41 (t, J=7.0, 3 H), 2.38 (s, 3 H), 4.38(q, J=7.0, 2 H), 6.80 (t, J=53.2, 1 H), 7.51 (d, J=4.4, 1 H), 7.82 (d,J=4.4, 1 H). ¹³C NMR 7.7, 14.5, 61.9, 109.5, 110.3 (t, J=236), 127.5,133.7, 134.1, 136.3, 158.7 (t, J=29), 161.9. ¹⁹F NMR −118.2 (J=53.5).LC/MS 6.60 min, [M+1]⁺ 288.

Lower Rf Product:5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidethyl ester. ¹H NMR (CDCl₃) 1.41 (t, J=7.0, 3 H), 2.37 (s, 3 H), 4.39(q, J=7.0, 2 H), 6.81 (t, J=52.7, 1 H), 7.50 (d, J=4.0, 1 H), 7.82 (d,J=4.0, 1 H). ¹³C NMR 7.7, 14.5, 61.8, 108.1 (t, J=238), 113.5, 128.4,133.6, 135.4, 136.2, 157.7, 159.8 (t, J=29), 161.9. ¹⁹F NMR −118.2(J=53.5). LC/MS 6.85 min, [M+1]⁺ 288.

Preparative Example 26

5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid

A solution of5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidethyl ester (Preparative Example 25, 1.0 g, 3.48 mmol) in THF (20 mL)was treated with an aqueous solution (5 mL) of lithium hydroxidemonohydrate (292 mg, 6.96 mmol) and allowed to stir for 20 hr. Thereaction was then evaporated to a small volume and treated with a 1 Naqueous hydrochloric acid solution to a pH of −2 and the resultingsolids filtered, washed with water and air dried to afford product as acolorless solid (900 mg, 99%). ¹H NMR (DMSO-d6) 2.29 (s, 3 H), 7.44 (t,J=51.9, 1 H), 7.66 (d, J=2.6, 1 H), 7.78 (d, J=2.6, 1 H). ¹³C NMR 7.7,108.1 (t, J=236), 115.0, 130.3, 134.3, 134.5, 137.4, 157.8, 159.6 (t,J=26), 163.1. ¹⁹F NMR −118.8 (J=51.5). LC/MS 5.41 min, [M+1]⁺ 260.

Preparative Example 27

5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-thiophene-2-carboxylic acid

Prepared from5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-thiophene-2-carboxylic acidethyl ester by the method described in Preparative Example 26 to affordproduct as a colorless solid (355 mg, 99%). ¹H NMR (DMSO-d6) 2.27 (s,3H), 7.33 (t, J=51.9, 1 H), 7.67 (d, J=4.0, 1 H), 7.80 (d, J=4.0, 1 H).¹⁹F NMR −118.8 (J=51.5). LC/MS 5.90 min, [M+1]⁺ 260.

Preparative Example 28

Dimethyl-(R)-1-piperidin-3-ylmethyl-amine, dihydrochloride

A solution of (S)-1-Boc-3-(aminomethyl)piperidine (429 mg, 2.0 mmol, CAS[140645-24-5], CHN Technologies, Woburn Mass., USA) in dichloromethane(10 mL) was treated with a 37% aqueous formaldehyde solution (551 μL,20.0 mmol) followed by sodium triacetoxyborohydride (4.23 g, 20.0 mmol).The mixture was stirred for 4 h then quenched with dichloromethane (10mL) and saturated aqueous solution of NaHCO₃ (50 mL). The organicportion was further washed with a brine solution (10 mL), then driedover MgSO₄, filtered, and evaporated in vacuo to afford product as anoil. LC/MS 1.10 min, [M+1]⁺ 243. The methylated intermediate wasdissolved in 1,4-dioxane (5 mL) and treated with a 4 N solution ofhydrogen chloride in 1,4-dioxane (5 mL) and stirred for 2 hr, afterwhich time product had precipitated out of solution. The reactionmixture was evaporated in vacuo and filtered with the aid of ethylether. The resulting solids were air dried to afford product as acolorless solid (290 mg, 67% overall). LC/MS 0.60 min, [M+1]⁺ 143.

Preparative Example 29

Dimethyl-(S)-1-piperidin-3-ylmethyl-amine, dihydrochloride

Prepared from (R)-1-Boc-3-(aminomethyl)piperidine (429 mg, 2.0 mmol, CAS[140645-23-4], CHN Technologies, Woburn Mass., USA) in the same manneras the R isomer described in Preparative Example 28. Colorless solid(306 mg, 71% overall). LC/MS 0.60 min, [M+1]⁺ 143.

Preparative Example 30

Methyl-piperidin-3-ylmethyl-carbamic acid 9H-fluoren-9-ylmethyl ester,hydrochloride

A solution of 9-fluorenylmethoxycarbonyl chloride (259 mg, 1.0 mmol) inTHF (3 mL), at 0-5° C., was treated with a THF solution (2 mL)containing 1-Boc-3-methylaminopiperidine (214 mg, 1.0 mmol, CAS[392331-89-4], CHN Technologies, Woburn Mass., USA) anddiisopropylethylamine (174 μL, 1.0 mmol). The reaction mixture wasallowed to stir for 1 h then placed in a 0-5° C. refrigerator for 16 h.After this time the reaction mixture was evaporated in vacuo,partitioned between EtOAc (10 mL) and a 1N aqueous HCl solution (10 mL),and the organic portion further washed with a saturated aqueous solutionof NaHCO₃ (10 mL) followed by a brine solution (10 mL). The organicportion was then dried over MgSO₄, filtered, and evaporated in vacuo toafford crude oil. The oil was chromatographed on silica gel withEtOAc/hexane (40%) to afford the Fmoc/Boc-protected intermediate as acolorless foam (409 mg, 94%). The intermediate was then dissolveddissolved in 1,4-dioxane (5 mL) and treated with a 4 N solution ofhydrogen chloride in 1,4-dioxane (5 mL), stirred for 2 hr, thenevaporated in vacuo to afford product as a colorless solid. LC/MS 4.42min, [M+1]⁺ 337.

Preparative Example 31

(3R)—N-methylpiperidine-3-carboxamide

A solution of D-Cbz-Nipecotic acid ((R)-Piperidine-1,3-dicarboxylic acid1-benzyl ester) (1.32 g, 5.0 mmol) in toluene (25 mL) was treated withDMF (20 μL) followed by oxalyl chloride (646 μL, 7.5 mmol). The reactionmixture was stirred for 3 hr and evaporated to an oil. The crude acidchloride was then dissolved in THF (20 mL), cooled to 0-5° C., andtreated with a 2 M THF solution of methylamine (7.5 mL, 15 mmol). Thereaction mixture was stirred for 2 hr, allowed to warm to roomtemperature and evaporated in vacuo to afford solids which were filteredwith the aid of water to afford Cbz-protected intermediate as acolorless solid (1.2 5 g, 91%). LC/MS 5.05 min, [M+1]⁺ 277. TheCbZ-protected intermediate (1.0 g, 3.62 mmol) was dissolved in EtOH (50mL), treated with a 10% palladium on carbon (50% water content) catalyst(750 mg) and hydrogenated at 60-70 psi hydrogen for 5 hr. The crudereaction mixture was then filtered through Celite, evaporated in vacuo,and redisolved in EtOH (10 mL) which was filtered through a nylonsyringe filter to remove residual catalyst. Evaporation of the solutionafforded crude product as a tacky solid (581 mg, 113%). LC/MS 0.68 min,[M+1]⁺ 143.

Preparative Example 32

(3S)—N-methylpiperidine-3-carboxamide

Prepared from L-Cbz-Nipecotic acid in the same manner as the D/(R)isomer described in Preparative Example 31. CBz-protected intermediateas a colorless solid (1.22 g, 88%). LC/MS 4.96 min, [M+1]⁺ 277.Evaporation of the mixture afforded crude product as a tacky solid (571mg, 111%). LC/MS 0.64 min, [M+1]⁺ 143.

Preparative Example 33

tert-butyl methyl[(3R)-piperidin-3-ylmethyl]carbamate

A solution of (3R)—N-methylpiperidine-3-carboxamide (Preparative Example31, 430 mg, 3.0 mmol) in acetonitrile (3 mL) was treated withtriethylamine (836 μL, 6.0 mmol) followed by benzylbromide (449 μL, 3.75mmol). The reaction mixture was allowed to stir for 24 hr thenpartitioned between EtOAc (20 mL) and a saturated aqueous solution ofNaHCO₃ (20 mL). The organic portion was washed with an additionalportion of NaHCO₃ solution followed by a brine solution (10 mL), thendried over MgSO₄, filtered, and evaporated in vacuo to affordN-benzylated intermediate as a waxy solid (459 mg, 66%). Theintermediate (450 mg, 1.94 mmol) was then dissolved in THF (20 mL) andtreated with a 1M THF solution of lithium aluminum hydride (2.9 mL, 2.91mmol) followed by heating at 60° C. for 8 hr. After this time thereaction mixture was cooled in an ice bath and quenched sequentiallywith water (0.5 mL), a 1 M NaOH solution (1 mL), and solid MgSO₄. Thereaction mixture was allowed to stir for 30 min followed by filtrationwith the aid of THF. Evaporation of the filtrate in vacuo afforded theN-benzylated amine intermediate as a clear liquid (403 mg, 95%). LC/MS0.66 min, [M+1]⁺ 219. The amine intermediate (400 mg, 1.83 mmol) wasthen dissolved in THF (10 mL) and treated with triethylamine (510 μL,3.66 mmol) followed by di-tert-butyl dicarbonate (600 mg, 1.83 mmol) andallowed to stir for 16 hr. After this time the reaction mixture waspartitioned between EtOAc (20 mL) and a saturated aqueous solution ofNaHCO₃ (20 mL). The organic portion was washed with an additionalportion of NaHCO₃ solution followed by a brine solution (10 mL), thendried over MgSO₄, filtered, and evaporated in vacuo to afford and oilthat was chromatographed on silica gel with EtOAc/hexanes (30%) thenMeOH/EtOAc (10%) as eluant to afford N-benzylated-N—BOC-protectedproduct as colorless oil (442 mg, 76%). LC/MS 4.42 min, [M+1]⁺ 319. Thedifferentially protected intermediate (440 mg, 1.38 mmol) was dissolvedin EtOH (50 mL), treated with palladium hydroxide on carbon (Pearlman'scatalyst, 500 mg) and hydrogenated at 60-70 psi hydrogen for 8 hr. Thecrude reaction mixture was then filtered through Celite, evaporated invacuo, and redisolved in EtOH (10 mL) which was filtered through a nylonsyringe filter to remove residual catalyst. Evaporation of the mixtureafforded crude product a clear colorless oil (298 mg, 94%, 45% overall).LC/MS 3.71 min, [M+1]⁺ 229.

Preparative Example 34

tert-butyl methyl[(3S)-piperidin-3-ylmethyl]carbamate

Prepared from (3S)—N-methylpiperidine-3-carboxamide (Preparative Example32) in the same manner as the (3R) isomer described in PreparativeExample 33. Product obtained as a colorless oil (340 mg, 51% overall).LC/MS 1.76 min, [M+1]⁺ 229

Preparative Example 35

(tert-butyl methyl[(3R)-piperidin-3-yl]carbamate

A solution of (R)-3-(tert-butoxycarbonylamino)piperidine (2.0 g, 10.0mmol) in THF (25 mL), at 0-5° C., was treated with triethylamine (1.67mL, 12.0 mmol) followed by benzyl chloroformate (1.55 mL, 11.0 mmol) andallowed to stir at that temperature for 24 hr. The reaction mixture wasthen evaporated in vacuo to ˜¼ volume and partitioned between EtOAc (20mL) and a 1 M HCl solution (20 mL). The organic portion was thensequentially washed with another portion of 1 M HCl (10 mL), a saturatedaqueous solution of NaHCO₃ (10 mL), and a brine solution (10 mL). Theorganic portion was then dried over MgSO₄, filtered, and evaporated invacuo to afford the N-Cbz protected intermediate as a colorless solid(3.2 g, 96%). LC/MS 6.58 min, [M+1]⁺ 335. The differentially protectedintermediate (1.67 g, 5.0 mmol) was then dissolved in DMF (20 mL) at0-5° C. and treated with a 60% suspension of sodium hydride (240 mg, 6.0mmol). The reaction mixture was allowed to warm to room temperature for10 min then recooled and iodomethane (374 μL, 6.0 mmol) added. After 2hr, and warming to room temperature, an additional amount (40 μL, 1.0mmol) of iodomethane was added and the reaction mixture allowed to stir16 hr. After this time the reaction mixture was evaporated in vacuo to˜¼ volume and partitioned between EtOAc (50 mL) and a water (50 mL). Theorganic portion was then washed with a brine solution (50 mL), driedover MgSO₄, filtered, and evaporated in vacuo to afford a residue whichwas chromatographed on silica gel with EtOAc/hexanes (20% then 30%) toafford the N-methylated intermediate as a colorless oil (1.59 g, 93%).LC/MS 6.92 min, [M+1]⁺ 349. The N-methylated intermediate (1.56 g, 4.48mmol) was dissolved in EtOH (50 mL), treated with 10% palladium oncarbon (250 mg) and hydrogenated at 60-70 psi hydrogen for 6 hr. Thecrude reaction mixture was then filtered through Celite, evaporated invacuo, and redisolved in EtOH (5 mL) which was filtered through a nylonsyringe filter to remove residual catalyst. Evaporation of the mixtureafforded crude product as a clear colorless oil. Product yield wastreated as quantitative for last step and used as reagent in a furtherreaction (Example 93). LC/MS 1.49 min, [M+1]⁺ 215.

Preparative Example 36

tert-butyl methyl[(3S)-piperidin-3-yl]carbamate

Prepared from (S)-3-(tert-butoxycarbonylamino)piperidine in the samescale and manner as the (3R) isomer described in Preparative Example 35.Yields were 96% and 93% for the first two steps. Product yield wastreated as quantitative for last step and used as reagent in a furtherreaction (Example 94). LC/MS 1.30 min, [M+1]⁺ 215.

COMPOUND PREPARATIONS Example 1

Piperidin-1-yl-[5-(5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

A solution of4,4,4-Trifluoro-1-[5-(piperidine-1-carbonyl)-thiophen-2-yl]-butane-1,3-dione(Preparative Example 3, 333 mg, 1 mmol) in glacial acetic acid (2.5 mL)was treated with hydroxylamine hydrochloride (73 mg, 1.05 mol) andheated at 80-90° C. for 24 hr, after which time the reaction wasevaporated and filtered with the aid of 30% EtOAc/hexanes to afford the5-hydroxy-4,5-dihydro-isoxazole intermediate (225 mg). The intermediatewas then dissolved in trifluoroacetic acid (2.5 mL) and heated at refluxfor 3 days. The reaction was then evaporated and the residuechromatographed on silica gel with EtOAc/hexanes (30 then 50%) as eluantto afford product as a colorless solid (105 mg, 32%). ¹H NMR (CDCl₃)1.65-1.73 (m, 6 H), 3.66-3.69 (m, 4 H), 6.95 (s, 1 H), 7.28 (d, J=4.0, 1H), 7.44 (d, J=4.0, 1 H). ¹³C NMR 24.7, 26.4, 47.0 (br), 103.7, 110.0,114.3 (q, J=267), 128.0, 129.0, 131.0, 140.9, 155.1 (q, J=40), 157.5,162.5. ¹⁹F NMR −64.6. LC/MS 6.63 min, [M+1]⁺ 331.

Example 2

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-piperidin-1-yl-methanone

Method A

Prepared from4,4,4-Trifluoro-2-methyl-1-[5-(piperidine-1-carbonyl)-thiophen-2-yl]-butane-1,3-dioneas described in Example 1. Chromatographed on silica gel withEtOAc/hexanes (40%) as eluant to afford product as a colorless solid (90mg, 26%). ¹H NMR (CDCl₃) 1.62-1.68 (m, 6 H), 2.33 (d, J=1.3, 3 H),3.64-3.67 (m, 4 H), 7.28 (d, J=4.0, 1 H), 7.41 (d, J=3.5, 1 H). ¹³C NMR7.9, 24.7, 26.3, 46.0 (br), 114.7, 118.8 (q, J=271), 128.0, 129.0,131.0, 140.3, 155.1 (q, J=40), 158.0, 162.3. ¹⁹F NMR −63.2. LC/MS 7.92min, [M+1]⁺ 344.

Method B

A solution of5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid(Preparative Example 14, 139 mg, 0.5 mmol) in toluene (5 mL) was treatedwith DMF (˜5 μL) followed by oxalyl chloride (85 μL, 1.0 mmol). Thereaction was allowed to stir for 2 hr at room temperature and 1 hr at40° C. The reaction was then concentrated in vacuo to afford crude acidchloride which was dissolved in THF (5 mL) and treated with a THFsolution (2 mL) of triethylamine (84 μL, 0.6 mmol) and piperidine (54μL, 0.55 mmol). The reaction was allowed to stir for 2 hr andconcentrated to approximately ¼ volume and partitioned between EtOAc (10mL) and an aqueous 1N hydrochloric acid solution (10 mL). The organicportion was then washed with a second portion of 1N hydrochloric acidsolution followed by a saturated aqueous solution of NaHCO₃ (10 mL) andbrine (10 mL). The organic solution was then dried over MgSO₄, filtered,and concentrated in vacuo to afford product which required no furtherpurification.

Example 3

Cyclohexyl-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

A solution of 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole(Preparative Example 21, 468 mg, 2.0 mmol) in dichloromethane (20 mL)was treated with FeCl₃ (324 mg, 2.0 mmol) followed by cyclohexylcarbonylchloride (268 μL, 05. mmol). The reaction was heated at reflux for 20hours followed by evaporation and partitioning between EtOAc (25 mL) andan aqueous 1N hydrochloric acid solution (25 mL). The organic portionwas then washed with a second portion of 1N hydrochloric acid solutionand brine, dried over MgSO₄, filtered, and concentrated in vacuo toafford crude product. The crude product was then chromatographed onsilica gel with EtOAc/hexanes (3%) as eluant to afford product as acolorless solid (240 mg, 35%). ¹H NMR (CDCl₃) 1.24-1.76 (m, 6 H),1.84-1.94 (m, 4 H), 2.37 (d, J=1.3, 3 H), 3.05-3.15 (m, 1 H), 7.54 (d,J=4.0, 1 H), 7.74 (d, J=4.0, 1 H). ¹³C NMR 7.9, 25.9, 26.0, 29.7, 47.8,114.8, 118.7 (q, J=271), 129.1, 131.6, 135.5, 146.0, 155.4 (q, J=41),158.0, 196.8. ¹⁹F NMR −63.1. LC/MS 7.92 min, [M+1]⁺ 344.

Example 4

Piperidin-1-yl-[4-(5-trifluoromethyl-isoxazol-3-yl)-phenyl]-methanone

A solution of 4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid(Preparative Example 11, 256 mg, 1.0 mmol) in toluene (10 mL) wastreated with DMF (˜5 μL) followed by oxalyl chloride (112 μL, 1.3 mmol).The reaction was allowed to stir for 3 hr then concentrated in vacuo toafford crude acid chloride which was dissolved in THF (5 mL) and treatedwith a THF solution (2 mL) of triethylamine (174 μL, 1.25 mmol) andpiperidine (109 μL, 1.1 mmol). The reaction was allowed to stir for 3 hrand concentrated in vacuo to afford crude product which was filteredwith the aid of water and solids air dried to afford product as acolorless solid (295 mg, 91%). ¹H NMR (CDCl₃) 1.55-1.70 (m, 6 H), 3.35(br s, 2 H), 3.73 (br s, 2 H), 7.04 (s, 1 H), 7.52 (d, J=8.3, 2 H), 7.86(d, J=7.9, 2 H). ¹³C NMR 24.7, 25.8, 26.8, 43.4, 49.0, 103.7, 118.0 (q,J=270), 127.3, 127.9, 128.4, 139.2, 162.2, 169.4. ¹⁹F NMR −64.6. LC/MS6.49 min, [M+1]⁺ 325.

Example 5

Cyclohexyl-[4-(5-trifluoromethyl-isoxazol-3-yl)-phenyl]-methanone

A solution ofN-Methoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3-yl)-benzamide(Preparative Example 15, 300 mg, 1.0 mmol) in THF (10 mL) was treatedwith a 1 N THF solution of cyclohexylmagnesium bromide (4 mL, 4 mmol)and stirred for 2 hr then quenched with a saturated ammonium chloridesolution (2 mL) and diluted with EtOAc (10 mL). The organic layer wasthen washed with brine (2×10 mL), dried over MgSO₄, filtered, evaporatedin vacuo and the residue chromatographed on silica gel withEtOAc/hexanes (5 then 10%) as eluant to afford product as a colorlesssolid (81 mg, 25%). ¹H NMR (CDCl₃) 1.26-1.58 (m, 5 H), 1.74-1.94 (m, 5H), 3.23-3.32 (m, 1 H), 7.09 (s, 1 H), 7.79 (d, J=8.3, 2 H), 7.87 (d,J=8.3, 2 H). ¹⁹F NMR −64.6. LC/MS 7.79 min, [M+1]⁺ 324.

Example 6

2,2-Dimethyl-1-[4-(5-trifluoromethyl-isoxazol-3-yl)-phenyl]-propan-1-one

Prepared fromN-Methoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3-yl)-benzamide and a1.7 N THF solution of tert-butylmagnesium bromide as described inExample 5. Chromatographed on silica gel with EtOAc/hexanes (5 then 10%)as eluant to afford product as a colorless solid (21 mg, 7%). ¹H NMR(CDCl₃) 1.37 (s, 9 H), 7.05 (s, 1 H), 7.79 (d, J=8.4, 2 H), 7.87 (d,J=7.9, 2 H). ¹⁹F NMR −64.6. LC/MS 7.28 min, [M+1]⁺298.

Example 7

[4-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-phenyl]-piperidin-1-yl-methanone

Prepared from 4-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-benzoic acidas described in Example 4. Chromatographed on silica gel withEtOAc/hexanes (20 then 25%) as eluant to afford product as a colorlesssolid (136 mg, 80%). ¹H NMR (CDCl₃) 1.49-1.64 (m, 6 H), 2.21 (d, J=1.8,3 H), 3.31 (br s, 2 H), 3.67 (br s, 2 H), 7.47 (d, J=7.9, 2 H), 7.60 (d,J=7.9, 2 H). ¹³C NMR 7.6, 24.7, 25.8, 26.7, 43.3, 48.9, 115.0, 118.9 (q,J=271), 127.6, 128.7, 128.8, 138.6, 154.8 (q, J=40), 163.2, 169.4. ¹⁹FNMR −63.3. LC/MS 6.65 min, [M+1]⁺ 339.

Example 8

Cyclohexyl-[4-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-phenyl]-methanone

Prepared fromN-Methoxy-N-methyl-4-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-benzamideas described in Example 5. Chromatographed on silica gel withEtOAc/hexanes (5%) as eluant to afford product as a colorless solid (130mg, 19%). ¹H NMR (CDCl₃) 1.23-1.56 (m, 5 H), 1.71-1.91 (m, 5 H), 2.27(d, J=0.9, 3 H), 3.22-3.30 (m, 1 H), 7.71 (d, J=7.9, 2 H), 8.04 (d,J=8.3, 2 H). ¹⁹F NMR −63.3. LC/MS 7.88 min, [M+1]⁺338.

Example 9

2,2-Dimethyl-1-[4-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-phenyl]-propan-1-one

Prepared fromN-Methoxy-N-methyl-4-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-benzamideand tert-butylmagnesium bromide as described in Example 5.Chromatographed on silica gel with EtOAc/hexanes (5%) as eluant toafford product as a colorless solid (53 mg, 9%). ¹H NMR (CDCl₃) 1.37 (s,9 H), 2.29 (d, J=1.3, 3 H), 7.68 (d, J=7.9, 2 H), 7.81 (d, J=8.3, 2 H).¹⁹F NMR −63.2. LC/MS 7.42 min, [M+1]⁺ 312.

Example 10

Piperidin-1-yl-[5-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-thiophen-2-yl]-methanone

A solution of 5-(Piperidine-1-carbonyl)-thiophene-2-carbonitrile(Preparative Example 18, 1.27 g, 5.77 mmol) in EtOH/water (20 mL/4 mL)was treated with sodium acetate (638 mg, 6.92 mmol) followed byhydroxylamine hydrochloride (481 mg, 6.92 mmol) and the resultingmixture heated at reflux for 2 hr then evaporated in vacuo. Theresulting solids were filtered with the aid of water and air dried for1.25 g (86%) of intermediate amidoxime. The intermediate amidoxime (1.15g, 4.54 mmol) was dissolved in toluene (30 mL), treated withtrifluoroacetic anhydride (1.89 mL, 13.62 mmol), and heated at refluxfor 3 hr. The reaction was allowed to cool to room temperature and stir16 hr then evaporated in vacuo and the residue chromatographed on silicagel with EtOAc/hexanes (20 then 40%) as eluant to afford product as acolorless solid (953 mg, 63%). ¹H NMR (CDCl₃) 1.66-1.73 (m, 6 H),3.66-3.70 (m, 4 H), 7.32 (d, J=4.0, 1 H), 7.80 (d, J=4.0, 1 H). ¹³C NMR24.6, 26.3, 45.5 (br), 48.3 (br), 116.0 (q, J=274), 128.2, 129.2, 130.7,142.5, 162.4, 165.0, 166.1 (q, J=45). ¹⁹F NMR −65.8. LC/MS 6.50 min,[M+1]⁺ 332.

Example 11

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic aciddimethylamide

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand dimethylamine hydrochloride by the method described in Example 2Method B utilizing an additional equivalent of triethylamine. Thereaction mixture was evaporated to a solid then triturated and filteredwith the aid of water to afford product as a colorless solid (110 mg,72%). ¹H NMR (CDCl₃) 2.37 (s, 3 H), 3.22 (br s, 6 H), 7.41 (d, J=4.0, 1H), 7.47 (d, J=4.0, 1 H). ¹³C NMR 7.9, 37.0 (br), 39.8 (br), 114.7,118.8 (q, J=271), 128.0, 129.7, 131.6, 140.9, 155.7 (q, J=41), 158.0,163.7. ¹⁹F NMR −63.2. LC/MS 6.03 min, [M+1]⁺ 305.

Example 12

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid(2-chloro-phenyl)-amide

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 2-chloroaniline by the method described in Example 2 Method B. Thereaction mixture was evaporated in vacuo, triturated and filtered withthe aid of water, then washed with an aqueous 1 N hydrochloric acidsolution followed by water. The crude solid was then chromatographed onsilica gel with EtOAc/hexanes (10 then 15%) as eluant to afford productas a colorless solid (42 mg, 43%). ¹H NMR (CDCl₃) 2.39 (d, J=1.3, 3 H),7.10 (td, J=7.9, 1.3, 1 H), 7.33 (td, J=7.9, 1.3, 1 H), 7.42 (dd, J=8.3,1.8, 1 H), 7.56 (d, J=4.0, 1 H), 7.69 (d, J=4.0, 1 H), 8.34 (s, 1 H),8.46 (dd, J=1.3, 1 H). ¹³C NMR 8.0, 114.8, 118.7 (q, J=271), 123.2,125.4, 128.2, 129.0, 129.3, 134.0, 134.3, 141.7, 155.5 (q, J=40), 157.8,159.0. ¹⁹F NMR −63.1. LC/MS 7.19 min, [M+1]⁺ 387.

Example 13

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidcyclopropylmethyl-amide

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand cyclopropylmethylamine by the method described in Example 2 MethodB. The reaction mixture was evaporated in vacuo, triturated and filteredwith the aid of water, then washed with an aqueous 1 N hydrochloric acidsolution followed by water. The crude solid was then triturated with a25% EtOAc/hexanes solution (3×1 mL) and air dried to afford product as acolorless solid (110 mg, 67%). ¹H NMR (CDCl₃) 0.27-0.32 (m, 2 H),0.55-0.61 (m, 2 H), 1.03-1.12 (m, 1 H), 2.37 (d, J=0.9, 3 H), 3.31 (d,J=5.7, 1 H), 3.33 (d, J=5.7, 1 H), 6.23 (br s, 1 H), 7.50 (d, J=4.0, 1H), 7.56 (d, J=4.0, 1 H). ¹⁹F NMR −63.1. LC/MS 6.5 min, [M+1]⁺ 331.

Example 14

[5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophen-2-yl]-piperidin-1-yl-methanone

Prepared from5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid(Preparative Example 26) and piperidine by the method described inExample 2 Method B. The reaction mixture was evaporated in vacuo, thenchromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluantto afford product as a colorless solid (54 mg, 66%). ¹H NMR (CDCl₃)1.65-1.72 (6, 3 H), 2.34 (s, 3 H), 3.67-3.70 (m, 4 H), 6.80 (t, J=53.2,1 H), 7.30 (d, J=4.0, 1 H), 7.43 (d, J=3.5, 1 H). ¹³C NMR 7.7, 24.7,26.3, ˜46 (br), 39.8 (br), 108.1 (t, J=238), 113.5, 127.6, 128.9, 131.6,140.1, 157.8, 159.5 (q, J=29), 162.7. ¹⁹F NMR −118.2 (J=53.5). LC/MS6.18 min, [M+1]⁺ 327.

Example 15

[5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-thiophen-2-yl]-piperidin-1-yl-methanone

Prepared from5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-thiophene-2-carboxylic acid(Preparative Example 27) and piperidine by the method described inExample 2 Method B. The reaction mixture was evaporated in vacuo, thenchromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluantto afford product as a colorless solid (110 mg, 72%). ¹H NMR (CDCl₃)1.66-1.72 (6, 3 H), 2.35 (s, 3 H), 3.67-3.71 (m, 4 H), 6.79 (t, J=53.2,1 H), 7.31 (d, J=4.0, 1 H), 7.45 (d, J=4.0, 1 H). ¹³C NMR 7.7, 24.7,26.3, ˜46 (br), 39.8 (br), 108.7, 110.3 (t, J=236), 126.8, 128.8, 130.6,140.6, 158.6 (q, J=30), 162.1, 162.5. ¹⁹F NMR −117.4 (J=53.5). LC/MS6.36 min, [M+1]⁺ 327.

Example 16

[5-(5-Methyl-[1,2,4]oxadiazol-3-yl)-thiophen-2-yl]-piperidin-1-yl-methanone

Prepared from 5-(5-Methyl-[1,2,4]oxadiazol-3-yl)-thiophene-2-carboxylicacid (CAS [133380-64-0]) as described in Example 4. Product was obtainedas a colorless solid (80 mg, 77%). ¹H NMR 1.60 (br m, 6 H), 2.59 (s, 3H), 3.61 (br m, 4 H), 7.22 (d, J=4.0, 1 H), 7.61 (d, J=3.5, 1 H). ¹³CNMR 12.5, 24.7, 26.3, 46.5 (br), 128.7, 129.1, 130.6, 141.0, 162.7,164.2, 177.0. LC/MS 5.51 min, [M+1]⁺ 278.

Example 17

(4-Hydroxy-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-hydroxypiperidine by the method described in Example 2 Method B.The reaction mixture was evaporated to a solid, triturated and filteredwith the aid of water, then washed with a 1 N aqueous hydrochloric acidsolution followed by water. The solid was air dried to afford product asa colorless solid (141 mg, 78%). ¹H NMR (CDCl₃) 1.58-1.69 (m, 2 H),1.93-2.00 (m, 2 H), 2.26 (br s, 1 H), 2.37 (s, 3 H), 3.44-3.52 (m, 2 H),4.00-4.12 (m, 3 H), 7.33 (d, J=4.0, 1 H), 7.46 (d, J=3.5, 1 H). ¹³C NMR7.9, 34.4, 42 (br), 66.9, 114.8, 118.7 (q, J=271), 128.0, 129.2, 131.2,140.1, 155.2 (q, J=40), 158.1, 162.8. ¹⁹F NMR −63.1. LC/MS 5.71 min,[M+1]⁺ 361.

Example 18

(4-Methoxy-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-methoxypiperidine by the method described in Example 2 Method B.The reaction mixture was evaporated to a solid, triturated and filteredwith the aid of water, then washed with a 1 N aqueous hydrochloric acidsolution followed by water. The solid was air dried to afford product asa colorless solid (151 mg, 81%). ¹H NMR (CDCl₃) 1.64-1.72 (m, 2 H),1.86-1.93 (m, 2 H), 2.33 (d, J=1.3, 3 H), 3.36 (s, 3 H), 3.47-3.58 (m, 3H), 3.87-3.95 (m, 2 H), 7.29 (d, J=3.5, 1 H), 7.42 (d, J=4.0, 1 H). ¹³CNMR 7.9, 30.9, 42 (br), 56.1, 75.2, 114.7, 118.7 (q, J=271), 128.0,129.1, 131.1, 140.3, 155.2 (q, J=40), 158.0, 162.7. ¹⁹F NMR −63.2. LC/MS6.31 min, [M+1]⁺ 375.

Example 19

(1,1-Dioxo-1lambda-6-thiomorpholin-4-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand thiomopholine 1,1-dioxide by the method described in Example 2Method B. The reaction mixture was evaporated to a solid, triturated andfiltered with the aid of water, then washed with a 1 N aqueoushydrochloric acid solution followed by water. The solid was air dried toafford product as a colorless solid (157 mg, 80%). ¹H NMR (DMSO-d6) 2.34(d, J=1.7, 3 H), 3.27 (obs m, 4 H), 4.00 (m, 4 H), 7.58 (d, J=3.5, 1 H),7.68 (d, J=4.0, 1 H). ¹³C NMR (incomplete, F-coupled carbons obscured bybaseline noise due to poor solubility) 8.0, ˜44 (br), 51.5, 116.6,128.0, 130.0, 130.8, 139.6, 158.5, 162.7. ¹⁹F NMR −62.2. LC/MS 5.80 min,[M+1]⁺ 395.

Example 20

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-piperazin-1-yl-methanone,hydrochloride

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand N-Boc-piperazine by the method described in Example 2 Method B. Thereaction mixture was evaporated to a solid, triturated and filtered withthe aid of water, then washed with a 1 N aqueous hydrochloric acidsolution followed by water. The solid was air dried then chromatographedon silica gel with EtOAc/hexanes (50%) as eluant to afford intermediateN-Boc protected product as a colorless solid (165 mg, 74%). TheBoc-protected intermediate was dissolved in 1,4-dioxane (5 mL) andtreated with a 4 N solution of hydrogen chloride in 1,4-dioxane andstirred for 12 hr, after which time the reaction mixture was evaporatedto approximately ½ volume and diluted with ethyl ether (20 mL). Theresulting solids were filtered and air dried to afford product as acolorless solid (131 mg, 69% overall). ¹H NMR (D₂O) 2.16 (s, 3 H), 3.22(m, 4 H), 3.87 (m, 4 H), 7.34 (d, J=4.0, 1 H), 7.42 (d, J=4.0, 1 H). ¹⁹FNMR −63.6. LC/MS 4.34 min, [M+1]⁺ 346.

Example 21

(4-Hydroxy-4-trifluoromethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-hydroxy-4-trifluoromethyl-piperidine by the method described inExample 2 Method B reversing the order of addition such that solid acidchloride was added to a THF solution of triethylamine and piperidinederivative. The reaction mixture was evaporated to a solid, trituratedand filtered with the aid of water, then washed with a 1 N aqueoushydrochloric acid solution followed by water. The solid was air driedand then chromatographed on silica gel with EtOAc/hexanes (50%) aseluant to afford product as a colorless solid (53 mg, 49%). ¹H NMR(DMSO-d6) 1.70-1.72 (m, 4 H), 2.34 (d, J=1.8, 3 H), 3.24 (br, 2 H), 4.19(br, 2 H), 6.17 (s, 1 H), 7.56 (d, J=4.0, 1 H), 7.65 (d, J=4.0, 1 H).19F NMR −83.5, −63.1. LC/MS 6.40 min, [M+1]+429.

Example 22

(3,3-Difluoro-azetidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 3,3-difluoroazetidine hydrochloride by the method described inExample 2 Method B reversing the order of addition such that solid acidchloride was added to a THF solution of triethylamine (containing andadditional 1.1 eq to neutralize the azetadinyl hydrochloride salt) andazetidine derivative. The reaction mixture was evaporated to a solid,triturated and filtered with the aid of water, then washed with a 1 Naqueous hydrochloric acid solution followed by water. The solid was airdried and then chromatographed on silica gel with EtOAc/hexanes (25 then50%) as eluant to afford product as a colorless solid (43 mg, 49%). ¹HNMR (CDCl₃) 2.37 (s, 3 H), 4.68 (br, 4 H), 4.19 (br, 2 H), 7.53 (s, 2H). ¹⁹F NMR −100.6, −63.1. LC/MS 6.42 min, [M+1]⁺ 353.

Example 23

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine by the method describedin Example 2 Method B reversing the order of addition such that solidacid chloride was added to a THF solution of triethylamine andpiperidine derivative. The reaction mixture was evaporated to a solid,triturated and filtered with the aid of water, then washed with asaturated aqueous NaHCO₃ solution followed by water to afford product asa pale yellow solid (88 mg, 85%). ¹H NMR (CDCl₃) 1.76 (m, 4 H),1.96-2.10 (m, 4 H), 2.37 (d, J=1.3, 3 H), 2.56-2.64 (m, 6 H), 3.80 (m, 2H), 4.48 (m, 1 H), 7.50 (d, J=4.0, 1 H), 7.57 (br, 1 H). ¹⁹F NMR −63.2.LC/MS 4.66 min, [M+1]⁺ 414.

Example 24

((R)-3-Hydroxy-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (R)-(+)-3-hydroxypiperidine hydrochloride by the method described inExample 2 Method B reversing the order of addition such that solid acidchloride was added to a THF solution of triethylamine (containing andadditional 1.1 eq. to neutralize the piperidinyl hydrochloride salt) andpiperidine derivative. The reaction mixture was evaporated to an oil andpartitioned between EtOAc (5 mL) and water (5 mL). The organic fractionwas further washed with brine (2×5 mL), dried over MgSO₄, filtered, andevaporated to an oil. The crude product was then chromatographed onsilica gel with EtOAc/hexanes (50 then 75 then 100%) as eluant to affordproduct as a colorless solid (41 mg, 45%). ¹H NMR (CDCl₃) 1.56-1.62 (m,1 H), 1.62-1.80 (m, 1 H), 1.83-2.10 (m, 2 H), 2.36 (d, J=1.3, 3 H), 2.86(br, 1 H), 3.50-3.76 (m, 4 H), 3.82-3.98 (m, 2 H), 7.39 (br d, J=4.0, 1H), 7.44 (d, J=4.0, 1 H). ¹³C NMR 7.9, 22.6, 32.5, ˜48 (br), ˜52 (br),66.2, 114.7, 118.7 (q, J=271), 128.0, 129.6, 131.3, 140.1, 155.2 (q,J=40), 157.9, 163.5. ¹⁹F NMR −63.2. LC/MS 5.65 min, [M+1]⁺ 361.

Example 25

((S)-3-Hydroxy-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared in the same manner as the R isomer. Colorless solid (27 mg,30%). LC/MS 5.68 min, [M+1]⁺ 361.

Example 26

((S)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand N-Boc-3-(S)-aminopiperidine by the method described in Example 2Method B. The reaction mixture was evaporated to a solid, triturated andfiltered with the aid of water, then washed with a 1 N aqueoushydrochloric acid solution followed by water. The solid was air driedthen chromatographed on silica gel with EtOAc/hexanes (50 then 75%) aseluant to afford intermediate N-Boc protected product as a colorlesssolid (87 mg, 76%). The Boc-protected intermediate was dissolved in1,4-dioxane (5 mL) and treated with a 4 N solution of hydrogen chloridein 1,4-dioxane and stirred for 12 hr, after which time the reactionmixture was evaporated to approximately ½ volume and diluted with ethylether (20 mL). The resulting solids were filtered and air dried toafford product as a colorless solid (70 mg, 71% overall). ¹H NMR (D₂O)1.36 (m, 1 H), 1.58 (m, 2 H), 1.90 (s, 3 H), 1.96 (m, 1 H), 3.08 (m, 3H), 3.21 (m, 1 H), 3.65 (m, 1H), 4.18 (br d, J=11.4, 1 H), 7.06 (br d, 1H), 7.09 (br d, 1H). ¹⁹F NMR −64.6. LC/MS 4.40 min, [M+1]⁺ 360.

Example 27

((R)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride

Prepared in the same manner as the S isomer. Colorless solid (15 mg, 20%overall). LC/MS 4.49 min, [M+1]⁺ 360.

Example 28

((R)-3-Dimethylamino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

A suspension of((R)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride (Example 26, 40 mg, 0.1 mmol) in dichloromethane (2 mL)was treated with a 37% aqueous formaldehyde solution (14 μL, 0.5 mmol)followed by sodium triacetoxyborohydride (128 mg, 0.6 mmol) and allowedto stir 24 hr. The reaction was then quenched by pouring onto a mixtureof dichloromethane (5 mL) and a saturated aqueous NaHCO₃ solution (5mL). The organic layer was separated, dried over MgSO₄, filtered, andevaporated to afford product as a colorless oil which solidified onstanding (34 mg, 87%). ¹H NMR (CDCl₃) 1.46-1.60 (m, 2 H), 1.83-1.90 (m,1 H), 2.02-2.12 (m, 1 H), 2.31 (s, 3 H), 2.34 (d, J=1.3, 3 H), 2.80-3.00(m, 2 H), 4.28 (br s, 1 H), 4.50 (br s, 1 H), 7.31 (d, J=4.0, 1 H), 7.43(d, J=4.0, 1 H). ¹³C NMR 7.9, 24.9, 42.4, ˜48 (br), 61.5, 115.0, 118.8(q, J=271), 128.0, 129.0, 131.2, 140.4 (q, J=41), 158.0, 162.8. ¹⁹F NMR−63.1. LC/MS 4.51 min, [M+1]⁺ 388.

Example 29

((S)-3-Dimethylamino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared in the same manner as the R isomer. Colorless solid (32 mg,83%). LC/MS 4.34 min, [M+1]⁺ 388.

Example 30

(3,5-Dimethyl-piperazin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 2,6-cis-dimethylpiperazine by the method described in Example 2Method B reversing the order of addition such that solid acid chloridewas added to a THF solution of triethylamine and piperazine derivative.The reaction mixture was evaporated to an oil and partitioned betweenEtOAc (5 mL) and water (5 mL). The organic fraction was further washedwith brine (2×5 mL), dried over MgSO₄, filtered, and evaporated to acolorless solid (79 mg, 85%). ¹H NMR (CDCl₃) 1.03 (d, J=4.8, 6 H),1.72-2.20 (m, 1 H), 2.29 (s, 3 H), 2.58 (br, 1 H), 2.78-2.90 (m, 2 H),4.25 (br, 2 H), 7.24-7.26 (m, 1 H), 7.37-7.39 (m, 1 H). ¹³C NMR 7.9,19.4, ˜50 (br obsc), 51.3, 114.7, 118.7 (q, J=271), 128.0, 129.3, 131.2,140.2, 155.1 (q, J=40), 157.9, 162.4. ¹⁹F NMR −63.2. LC/MS 4.43 min,[M+1]⁺374.

Example 31

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid(3-chloro-pyridin-4-yl)-amide

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-amino-3-chloropyridine by the method described in Example 2 MethodB reversing the order of addition such that solid acid chloride wasadded to a THF solution of triethylamine and pyridine derivative. Thereaction mixture was evaporated to a solid, triturated and filtered withthe aid of water, then washed with a saturated aqueous NaHCO₃ solutionfollowed by water to afford product as a colorless solid (80 mg, 83%).¹H NMR (CDCl₃) 2.40 (s, 3 H), 7.59 (d, J=4.0, 1 H), 7.73 (d, J=4.0, 1H), 8.46 (s, 3 H), 8.59 (s, 1 H). ¹³C NMR 7.9, 114.5, 114.7, 118.6 (q,J=271), 129.0, 129.7, 135.2, 140.4, 141.0, 149.4, 149.6, 155.6 (q,J=40), 157.6, 159.3. ¹⁹F NMR −63.1. LC/MS 6.68 min, [M+1]⁺ 388.

Example 32

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid(4-chloro-pyridin-3-yl)-amide

A solution of 3-amino-4-chloropyridine (129 mg, 1.0 mmol) in THF (2 mL)was treated with solid5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonylchloride (148 mg, 0.5 mmol, as prepared in Example 2 Method B) andallowed to stir for 1 hr. The reaction was then evaporated and theresidue chromatographed on silica gel with EtOAc/hexanes (70%) as eluantto afford product as a colorless solid (31 mg, 16%). ¹H NMR (CDCl₃) 2.39(d, J=1.5, 3 H), 7.39 (d, J=5.3, 1 H), 7.56 (d, J=7.56, 4.1, 1 H), 7.72(d, J=4.1, 1 H), 8.22 (s, 1 H), 8.33 (d, J=4.7, 1 H), 9.61 (s, 1 H). ¹³CNMR 8.0, 114.8, 118.7 (q, J=271), 129.0, 129, 7, 132.9, 134.6, 140.5,143.8, 146.1, 157.7, 159.0, ¹⁹F NMR −63.1. LC/MS 6.34 min, [M+1]⁺ 388.

Example 33

N-{(R)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide

A suspension of((R)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride (Example 27, 79 mg, 0.2 mmol) in THF (2 mL) was treatedwith triethylamine (70 μL, 0.5 mmol) followed by acetyl chloride (22 μL,0.3 mmol). The reaction mixture was allowed to stir 48 hr, evaporatedand chromatographed on silica gel with EtOAc then MeOH/EtOAc (10%) aseluant to afford product as a colorless solid (66 mg, 83%). ¹H NMR(CDCl₃) 1.65 (m, 2 H), 1.81 (m, 1 H), 1.95 (s, 3 H), 2.00 (obs m, 1 H),2.33 (d, J=1.3, 3 H), 3.30 (m, 2 H), 3.98 (m, 2 H), 4.10 (br d, J=11.0,1 H), 6.10 (br d, J=6.6, 1 H), 7.43 (d, J=4.0, 1 H), 7.49 (br s, 1 H).¹³C NMR 7.9, 23.5, 30.1, 46.5, 51.0 (br), 114.8, 118.7 (q, J=271),128.3, 129.7, 131.7, 140.1, 155.2 (J=40), 157.9, 163.3, 170.3 ¹⁹F NMR−63.1. LC/MS 5.72 min, [M+1]⁺ 402.

Example 34

N-{(S)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide

Prepared in the same manner as the R isomer. Colorless solid (66 mg,83%). LC/MS 5.60 min, [M+1]⁺ 402.

Example 35

N-{(R)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-methanesulfonamide

A suspension of((R)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride (Example 27, 79 mg, 0.2 mmol) in THF (2 mL) was treatedwith triethylamine (63 μL, 0.45 mmol) followed by methanesulfonylchloride (19 μL, 0.24 mmol). The reaction mixture was allowed to stir 48h, evaporated, and chromatographed on silica gel with EtOAc as eluant toafford product as a colorless foam (61 mg, 70%). ¹H NMR (CDCl₃) 1.68 (m,2 H), 1.88 (m, 2 H), 2.02 (m, 1 H), 2.33 (d, J=1.8, 3 H), 2.98 (s, 3 H),3.46 (m, 2 H), 3.57 (m, 1 H), 3.84 (m, 1 H), 4.05 (d, J=12.7, 1 H), 5.45(d, J=7.5, 1 H), 7.39 (d, J=4.0, 1 H), 7.43 (d, J=3.5, 1 H). ¹³C NMR7.9, 23.4, 31.6, 41.9, 47 (br), 52 (br), 49.9, 114.8, 118.7 (q, J=271),128.2, 129.8, 131.8, 139.6, 155.2 (q, 40), 157.9, 163.5. ¹⁹F NMR −63.1.LC/MS 5.82 min, [M+1]⁺ 438.

Example 36

N-{(S)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-methanesulfonamide

Prepared in the same manner as the R isomer. Colorless foam (57 mg,65%). LC/MS 5.82 min, [M+1]⁺ 438.

Example 37

((R)-2-Methyl-piperazin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-N-Boc-2-(R)-methyl-piperazine by the method described in Example 2Method B. The reaction mixture was evaporated to a solid, triturated andfiltered with the aid of water, then washed with a 1 N aqueoushydrochloric acid solution followed by water. The solid was air dried toafford intermediate N-Boc protected product as a colorless solid (106mg, 92%). The Boc-protected intermediate was dissolved in a 4 N solutionof hydrogen chloride in 1,4-dioxane (2 mL) and stirred for 2 hr, afterwhich time the reaction mixture was evaporated to approximately ¼ volumeand diluted with ethyl ether (4 mL). The resulting solids were filteredand air dried to afford product as a colorless solid (85 mg, 86%overall). ¹H NMR (D₂O) 1.27 (d, J=7.5, 3 H), 2.02 (s, 3 H), 3.04 (dt,J=12.7, 3.1, 1 H), 3.12-3.18 (m, 2 H), 3.30-3.50m (m, 2 H), 4.21 (d,J=14.5, 1 H), 7.23 (s, 2 H). ¹⁹F NMR −64.1. LC/MS 4.50 min, [M+1]⁺ 360.

Example 38

((S)-2-Methyl-piperazin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride

Prepared in the same manner as the R isomer. Colorless solid (81 mg,79%). LC/MS 4.37 min, [M+1]⁺ 360.

Example 39

((R)-2-Hydroxymethyl-piperazin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-N-Boc-2-(R)-hydroxymethyl-piperazine by the method described inExample 2 Method B. The reaction mixture was evaporated to a solid,triturated and filtered with the aid of water, then washed with a 1 Naqueous hydrochloric acid solution followed by water. The solid was airdried afford intermediate N-Boc protected product as a colorless solid(102 mg, 86%). The Boc-protected intermediate was dissolved in a 4 Nsolution of hydrogen chloride in 1,4-dioxane (2 mL) and stirred for 2hr, after which time the reaction mixture was evaporated toapproximately ¼ volume and diluted with ethyl ether (4 mL). Theresulting solids were filtered and air dried to afford product as acolorless solid (85 mg, 83% overall). ¹H NMR (D₂O) 2.17 (s, 3 H),3.26-3.46 (m, 3 H), 3.60-3.80 (m, 3 H), 4.00-4.04 (m, 1 H), 4.48 (dd,J=12.7, 5.3, 1 H), 4.60 (obs dd, J=13.2, 3.5, 1 H), 7.46 (d, J=4.3, 1H), 7.82 (d, J=4.0, 1 H). ¹⁹F NMR −63.5. LC/MS 3.89 min, [M+1]⁺ 376.

Example 40

(S)-Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-amino-3-chloropyridine by the method described in Example 2 MethodB reversing the order of addition such that solid acid chloride wasadded to a THF solution of triethylamine and(S)-1,4-diazabicyclo[4.3.0]nonane. The reaction mixture was evaporatedto a solid, triturated and filtered with the aid of water, then washedwith a saturated aqueous NaHCO₃ solution followed by water to affordproduct as a yellow colored solid (82 mg, 85%). ¹H NMR (CDCl₃) 1.34-1.48(m, 1 H), 1.70-1.90 (m, 3 H), 1.92-2.20 (m, 1 H), 2.10-2.26 (m, 2 H),2.32 (d, J=1.3, 3 H), 2.80 (br s, 1 H), 3.03-3.11 (m, 2 H), 3.20 (obs brs, 1 H), 4.40 (br s, 2 H), 7.29 (d, J=4.0, 1 H), 7.41 (d, J=3.5, 1 H).¹³C NMR 7.9, 21.3, 27.5, 30.0, ˜48 (br), 51.8, 53.5, 62.8, 114.7, 118.7(q, J=271), 128.0, 129.3, 131.2, 140.2, 155.2 (q, J=40), 157.9, 162.9.¹⁹F NMR −63.1. LC/MS 4.34 min, [M+1]⁺ 386.

Example 41

(4-Methyl-piperazin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

A suspension of5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidacid (90 mg, 0.33 mmol) in dichloromethane (2 mL) was treated with4-dimethylaminopyridine (100 mg, 0.82 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157 mg,0.82 mmol), and N-methylpiperazine (0.1 mL, 0.90 mmol). A furtherportion of dichloromethane (2 mL) and DMF (5 drops) was added and thereaction stirred at room temperature for 20 hr. The reaction mixture waspartitioned between dichloromethane (20 mL) and a 1 N aqueoushydrochloric acid solution (20 mL). The organic layer was further washedwith a a 1 N aqueous hydrochloric acid solution (20 mL), then a 5%aqueous sodium hydroxide solution (2×20 mL) followed by brine (20 mL).The organic layer was dried over Na₂SO₄, filtered, and concentrated invacuo to afford a yellow colored oil (66.5 mg). Gradient columnchromatography on silica with MeOH/EtOAc (10 to 50%) as eluant to affordproduct as a colorless solid (26 mg, 22%). ¹H NMR (CD₃OD) 2.40 (s, 3 H),2.42 (d, J=1.4, 3 H), 2.59 (t, J=5.0, 4 H), 3.84 (t, J=5.0, 4 H), 7.52(d, J=3.8, 1 H), 7.64 (d, J=3.8, 1 H). ¹⁹F NMR −64.8. LC/MS 4.48 min,[M+1]⁺ 360.

Example 42

(4-Methyl-[1,4]diazepan-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 1-methyl-[1,4]diazepane by the method described in Example 41.Yellow colored solid (49 mg, 37%). ¹H NMR (CDCl₃) 1.97-2.05 (m, 2 H),2.36 (d, J=1.4, 3 H), 2.40 (s, 3 H), 2.62 (br s, 2 H), 2.74 (br s, 2 H),3.80 (br s, 2 H), 7.37 (br s, 1 H), 7.45 (d, J=3.8, 1 H). ¹⁹F NMR −63.1.LC/MS 4.43 min, [M+1]⁺ 374.

Example 43

(4-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand piperidin-4-yl-carbamic acid tert-butyl ester by the methoddescribed in Example 41. N-Boc intermediate. The crude product waschromatographed on silica with EtOAc/hexanes (25 then 50%) as eluant toafford intermediate as a colorless solid (110 mg, 68%):LC/MS 6.70 min,[M+1]⁺ 460. The N-Boc intermediate (84.8 mg, 0.18 mmol) in EtOAc (4 mL)was treated with a 4 N solution of hydrogen chloride in 1,4-dioxane (2mL) and stirred for 22 hr. The resulting precipitate was filtered andwashed with EtOAc (2×10 mL). The solids were then partitioned between a2.5% aqueous sodium hydroxide solution (40 mL) and dichlromethane (20mL). The aqueous phase was further extracted with dichlromethane (2×20mL) and the combined organics dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford product as a colorless solid (56 mg, 57%overall). ¹H NMR (CD₃OD) 1.36-1.50 (m, 2 H), 1.98 (d, J=11.8, 2 H), 2.43(s, 3 H), 3.02 (m, 1 H), 3.18 (br s, 2 H), 4.40 (br s, 2 H), 7.49 (d,J=3.6, 1 H), 7.64 (d, J=3.8, 1 H). ¹⁹F NMR −64.8. LC/MS 4.51 min, [M+1]⁺360.

Example 44

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-phenyl-methanone

Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole andbenzoyl chloride by the method described in Example 3. Crude product waschromatographed on silica gel with EtOAc/hexanes (10 then 20%) as eluantto afford product as a colorless solid (118 mg, 70%). ¹H NMR (CDCl₃)2.33 (d, J=1.3, 3 H), 7.43-7.59 (m, 4 H), 7.62 (d, J=4.0, 1 H),7.80-7.83 (m, 2 H). ¹³C NMR 7.9, 118.7 (q, J=271), 128.8, 128.9, 129.4,133.0, 134.8, 136.3, 137.7, 145.8, 155.5 (q, J=40), 157.9, 188.0. ¹⁹FNMR −63.1. LC/MS 7.29 min, [M+1]⁺ 338.

Example 45

4-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-benzonitrile

Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and4-cyanobenzoyl chloride by the method described in Example 3. Crudeproduct was chromatographed on silica gel with EtOAc/hexanes (10 then20%) as eluant to afford product as a colorless solid (130 mg, 36%). ¹HNMR (CDCl₃) 2.42 (d, J=1.3, 3 H), 7.62 (d, J=4.0, 1 H), 7.67 (d, J=4.0,1 H), 7.85 (d, J=8.3, 1 H), 7.98 (d, J=7.9, 1 H). ¹³C NMR 8.0, 114.9,116.3, 118.7 (q, J=271), 118.0, 129.1, 129.8, 132.7, 135.3, 137.6,141.1, 144.6, ˜155 (q, obscured due to baseline noise), 157.7, 186.4.¹⁹F NMR −63.1. LC/MS 7.08 min, [M+1]⁺ 363.

Example 46

(3-Hydroxymethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 3-piperidinemethanol by the method described in Example 2 Method Breversing the order of addition such that solid acid chloride was addedto a THF solution of triethylamine and piperidine derivative. Thereaction mixture was evaporated to an oil then partitioned between EtOAc(5 mL) and water (5 mL). The organic fraction was further washed withbrine (2×5 mL), dried over MgSO₄, filtered, and evaporated to an oil.The crude product was then chromatographed on silica gel withEtOAc/hexanes (75%) as eluant to (190 mg, 75%). ¹H NMR (CDCl₃) 1.28-1.35(m, 1 H), 1.44-1.56 (m, 1 H), 1.67-1.82 (m, 3 H), 2.28 (d, J=0.9, 3 H),2.99 (dd, J=13.2, 9.7, 1 H), 3.32 (br s, 1 H), 3.41-3.52 (m, 2 H), 4.10(br s, 1 H), 4.21 (d, J=11.4, 1 H), 7.29 (d, J=4.0, 1 H), 7.37 (d,J=4.0, 1 H). ¹³C NMR 7.8, 24.9, 27.2, 39.1, ˜49 (br), 64.5, 114.8, 118.7(q, J=271), 128.1, 129.3, 131.2, 140.3, 155.0 (q, J=40), 157.9, 162.9.¹⁹F NMR −63.2. LC/MS 5.91 min, [M+1]⁺ 375.

Example 47

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-morpholin-4-yl-methanone

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand morpholine by the method described in Example 2 Method B reversingthe order of addition such that solid acid chloride was added to a THFsolution of triethylamine and piperidine derivative. The reactionmixture was evaporated to a solid, triturated and filtered with the aidof water, then washed with a 1 N aqueous hydrochloric acid solutionfollowed by water. The solid was air dried to afford product as acolorless solid (66 mg, 95%). ¹H NMR (CDCl₃) 2.34 (d, J=1.3, 3 H),3.71-3.77 (m, 8 H), 7.32 (d, J=4.0, 1 H), 7.43 (d, J=4.0, 1 H). ¹³C NMR7.9, ˜48 (br), 67.0, 114.7, 118.7 (q, J=271), 128.0, 129.5, 131.7,139.5, 157.9, 162.8. ¹⁹F NMR −63.2. LC/MS 5.93 min, [M+1]⁺ 347.

Example 48

1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidine-4-carbonitrile

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-cyanopiperidine by the method described in Example 2 Method Breversing the order of addition such that solid acid chloride was addedto a THF solution of triethylamine and piperidine derivative. Thereaction mixture was evaporated to a solid, triturated and filtered withthe aid of water, then washed with a 1 N aqueous hydrochloric acidsolution followed by water. The solid was air dried then chromatographedon a short column of silica gel with EtOAc as eluant to afford productas a colorless solid (91 mg, 61%). ¹H NMR (CDCl₃) 1.91-2.06 (m, 4 H),2.37 (d, J=1.3, 3 H), 2.97-3.03 (m, 1 H), 3.71-3.79 (m, 2 H), 3.90-3.98(m, 2 H), 7.34 (d, J=4.0, 1 H), 7.47 (d, J=4.0, 1 H). ¹³C NMR 7.9, 26.5,28.9, 43.6, 114.8, 118.7 (q, J=271), 120.8, 128.1, 129.5, 131.7, 139.4,155.2 (q, J=40), 157.8, 162.9. ¹⁹F NMR −63.2. LC/MS 6.18 min, [M+1]⁺370.

Example 49

1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidine-3-carboxylicacid amide

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 3-piperidinecarboxamide by the method described in Example 2 MethodB reversing the order of addition such that solid acid chloride wasadded to a THF solution of triethylamine and piperidine derivative. Thereaction mixture was evaporated to a solid, triturated and filtered withthe aid of water, then washed with a 1 N aqueous hydrochloric acidsolution followed by water. The solid was air dried to afford product asa colorless solid (120 mg, 97%). ¹H NMR (DMSO-d6) 1.36-1.49 (m, 1 H),1.55-1.75 (m, 2 H), 1.89-1.93 (m, 1 H), 2.35 (d, J=1.8, 3 H), 3.03 (brs, 2 H), 4.10 (br s, 2 H), 6.90 (s, 1 H), 7.37 (s, 1 H), 7.51 (d, J=4.0,1 H), 7.67 (d, J=4.0, 1 H). ¹⁹F NMR −62.2. LC/MS 5.54 min, [M+1]⁺ 388.

Example 50

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-(3-morpholin-4-yl-piperidin-1-yl)-methanone,hydrochloride

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-piperidin-3-yl-morpholine, di-hydrochloride by the methoddescribed in Example 2 Method B reversing the order of addition suchthat solid acid chloride was added to a THF solution of triethylamineand piperidine derivative. An additional 2 equivalents of triethylaminewas used. The reaction mixture was evaporated to an oil, triturated andfiltered with the aid of water, then with a saturated aqueous NaHCO₃solution. The residual oil was then dissolved in EtOAc (2 mL), driedover MgSO₄, filtered, and evaporated to an oil. The crude oil was thendissolved in diethyl ether (1 mL) and treated with a 4 N solution ofhydrogen chloride in 1,4-dioxane to precipitate product as a colorlesssolid. The solid was filtered with the aid of diethyl ether and airdried to afford product as a colorless solid (61 mg, 65%). LC/MS 4.66min, [M+1]⁺ 430.

Example 51

[3-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 1-Methyl-4-piperidin-3-yl-piperazine, tri-hydrochloride by themethod described in Example 2 Method B reversing the order of additionsuch that solid acid chloride was added to a THF solution oftriethylamine and piperidine derivative. An additional 3 equivalents oftriethylamine was used. The reaction mixture was evaporated to an oil,triturated and filtered with the aid of water, then with a saturatedaqueous NaHCO₃ solution. The residual oil was then dissolved in EtOAc (2mL), dried over MgSO₄, filtered, and evaporated to an oil. The crude oilwas then dissolved in diethyl ether (1 mL) and treated with a 4 Nsolution of hydrogen chloride in 1,4-dioxane to precipitate product as acolorless solid. The solid was filtered with the aid of diethyl etherand air dried to afford product as a colorless solid (47 mg, 53%). LC/MS4.62 min, [M+1]⁺ 443.

Example 52

(3-Dimethylaminomethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride

A solution of(3-Hydroxymethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone(Example 46, 170 mg, 0.454 mmol) and triethylamine (111 μL, 0.795 mmol)in CH₂Cl₂ (4 mL) at −10 to −5° C., was treated with methanesulfonylchloride (53 μL, 0.681 mmol) and allowed to stir for 1 hr. The reactionmixture was then quenched with CH₂Cl₂ (4 mL) and water (4 mL), and theorganic portion further washed with a 1 N aqueous hydrochloric acidsolution (2×3 mL) followed by a saturated aqueous NaHCO₃ solution (2×3mL) and brine (3 mL). The organic layer was then dried over MgSO₄,filtered, and evaporated to the Methanesulfonic acid1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-ylmethylester intermediate as an oil (180 mg, 88%). A solution of theintermediate sulfonate (60 mg, 0.1326 mmol) in acetonitrile (2 mL) wastreated with a 2 N THF solution of dimethylamine (265 μL, 0.5304 mmol)and heated at 45° C. in a sealed tube for 2 weeks. The reaction was thenevaporated and the resulting oil triturated with water (3×2 mL) thendissolved in EtOAc (2 mL), dried over MgSO₄, filtered, and evaporated.The crude oil product was then dissolved in diethyl ether (2 mL) andtreated with a 4 N solution of hydrogen chloride in 1,4-dioxane toprecipitate product as a colorless solid. The solid was filtered withthe aid of diethyl ether and air dried to afford product as a colorlesssolid (30 mg, 52%). ¹H NMR (CDCl₃) 1.12-1.29 (m, 1 H), 1.44-1.58 (m, 1H), 1.67-1.79 (m, 2 H), 1.80-1.90 (m, 1 H), 2.05-2.15 (m, 8 H), 2.29 (d,J=1.3, 3 H), 2.70 (br s, 1 H), 3.00 (br s, 1 H), 4.10-4.40 (br m, 2 H),7.28 (d, J=3.5, 1 H), 7.38 (d, J=3.5, 1 H). ¹³C NMR 7.9, 25.2, 29.7,34.9, 46.1, 63.3, 114.7, 118.8 (q, J=271), 128.0, 129.1, 131.0, 140.8,155.1 (q, J=40), 158.0, 162.8. ¹⁹F NMR −63.1. LC/MS 4.52 min, [M+1]⁺402.

Example 53

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-(3-morpholin-4-ylmethyl-piperidin-1-yl)-methanone

Prepared from Methanesulfonic acid1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-ylmethyl(60 mg, 0.1326 mmol) and morpholine (46 μL, 0.530 mmol) by the methoddescribed in Example 52. The reaction mixture was heated at 65° C. for10 days and isolated as the free-base oil (51 mg, 86%). ¹H NMR (CDCl₃)1.12-1.29 (m, 1 H), 1.44-1.58 (m, 1 H), 1.68-1.90 (m, 3 H), 2.12-2.16(m, 2 H), 2.20-2.32 (m, 5 H), 2.34-2.42 (m, 2 H), 2.76 (br s, 1 H), 3.04(br t, J=11.4, 1 H), 3.57 (s, 4 H), 4.18 (br s, 1 H), 4.32 (br s, 1 H),7.29 (d, J=4.0, 1 H), 7.37 (d, J=3.5, 1 H). ¹⁹F NMR −63.1. LC/MS 4.62min, [M+1]⁺ 444.

Example 54

[3-(4-Methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from Methanesulfonic acid1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-ylmethyl(60 mg, 0.1326 mmol) and N-Methylpiperazine (58 μL, 0.530 mmol) by themethod described in Example 52. The reaction mixture was heated at 65°C. for 10 days and isolated as the free-base oil (44 mg, 73%). ¹H NMR(CDCl₃) 1.14-1.30 (m, 1 H), 1.42-1.58 (m, 1 H), 1.66-1.90 (m, 3 H),2.10-2.45 (m, 16 H), 2.34-2.42 (m, 2 H), 2.76 (br s, 1 H), 3.02 (br t,J=10.5, 1 H), 4.18 (br s, 1 H), 4.28 (br s, 1 H), 7.31 (br d, J=3.5, 1H), 7.38 (d, J=4.0, 1 H). ¹⁹F NMR −63.1. LC/MS 4.64 min, [M+1]⁺ 457.

Example 55

2-Dimethylamino-N-{(S)-1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide

A solution of((S)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride (Example 26, 79 mg, 0.20 mmol) in THF (3 mL) was treatedwith dimethylaminoacetyl chloride hydrochloride (40 mg, 0.24 mmol)followed by triethylamine (62 μL, 0.44 mmol). The resulting mixture wasstirred for 16 hr, evaporated to an oil, and dissolved in water (3 mL).The solution was then basified with a saturated aqueous K₂CO₃ solutionand the precipitated product filtered, washed with water, and air driedto afford product as a colorless solid (69 mg, 78%). ¹H NMR (CDCl₃)1.62-1.72 (m, 2 H), 1.78-1.84 (m, 1 H), 1.94-2.04 (m, 1 H), 2.25 (s, 6H), 2.32 (d, J=1.3, 3 H), 2.49 (s, 2 H), 3.24-3.40 (m, 2 H), 3.94-4.04(m, 2 H), 4.12 (br d, J=13.2, 1 H), 7.23 (br d, J=7.5, 1 H), 7.44 (d,J=4.0, 1 H), 7.47 (br s, 1 H). ¹³C NMR 7.9, 23.5, 30.4, 45.6, 46.2, ˜51(br), 63.2, 114.8, 118.8 (q, J=271), 128.3, 129.5, 131.6, 140.2, 155.1(q, J=40), 157.9, 163.1, 170.7. ¹⁹F NMR −63.1. LC/MS 4.59 min, [M+1]⁺445.

Example 56

N-{(S)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-2-morpholin-4-yl-acetamide

A solution of((S)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride (Example 26, 79 mg, 0.20 mmol) and triethylamine (69 μL,0.42 mmol) in THF (3 mL) was treated with chloroacetyl chloride (18 μL,0.22 mmol), stirred for 1 hr and evaporated to a solid. The solid wastriturated and filtered with the aid of water, then air dried to providethe2-Chloro-N-{(S)-1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamideintermediate as a colorless solid (75 mg, 86%). LC/MS 6.13 min, [M+1]⁺436. The chloroacetyl intermediate (35 mg, 0.08 mmol) was dissolved inacetonitrile (3 mL) containing anhydrous K₂CO₃, treated with morpholine(14 μL, 0.16 mmol), and stirred for 3 days. The reaction mixture wasthen evaporated and treated with water to provide an oil which was thentriturated with water (3×2 mL), dissolved in EtOAc (4 mL), dried overMgSO₄, filtered, and evaporated to afford product as an oil (34 mg,87%). ¹H NMR (CDCl₃) 1.62-1.76 (m, 3 H), 1.88-1.98 (m, 1 H), 2.29 (d,J=1.3, 3 H), 2.45-2.48 (m, 4 H), 2.93 (s, 2 H), 3.52 (br s, 1 H),3.63-3.67 (m, 4 H), 3.72-3.92 (m, 2 H), 3.98-4.08 (m, 1 H), 7.32 (br s,1 H), 7.41 (s, 2 H). ¹⁹F NMR −63.1. LC/MS 4.68 min, [M+1]⁺ 487.

Example 57

2-(4-Methyl-piperazin-1-yl)-N-{(S)-1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide

2-Chloro-N—{(S)-1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide(35 mg, 0.08 mmol, as prepared in Example 56) was dissolved inacetonitrile (3 mL) containing anhydrous K₂CO₃, treated withN-methylpiperazine (18 μL, 0.16 mmol), and stirred for 3 days. Thereaction mixture was then evaporated and treated with water to provide ahomogeneous solution which was extracted with EtOAc (2×4 mL), dried overMgSO₄, filtered, and evaporated to afford product as an foam (34 mg,85%). ¹H NMR (CDCl₃) 1.60-1.76 (m, 3 H), 1.88-1.98 (m, 1 H), 2.22 (s, 3H), 2.29 (d, J=1.3, 3 H), 2.32-2.52 (m, 8 H), 2.92 (s, 2 H), 3.52 (br s,1 H), 3.48 (br s, 2 H), 3.72-4.46 (m, 3 H), 7.32-7.44 (br m, 3 H). ¹⁹FNMR −63.1. LC/MS 4.59 min, [M+1]⁺ 500.

Example 58

(3-Hydroxy-azetidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 3-hydroxyazetidine hydrochloride by the method described in Example41. Colorless solid (78 mg, 73%). ¹H NMR (DMSO-d6) 2.38 (s, 3H),3.77-3.90 (m, 1H), 4.19-4.38 (m, 2H), 4.52-4.63 (m, 1H), 4.65-4.78 (m,1H), 5.88 (d, J=5.9, 1H), 7.62 (d, J=4.0, 1H), 7.73 (d, J=4.0, 1H). ¹³CNMR 7.4, 58.9, 60.6, 62.5, 116.0 (q, J=2), 118.5 (q, J=271), 130.3,130.5, 131.0, 140.2, 153.2 (q, J=40), 157.9, 160.8. ¹⁹F NMR −62.3. LC/MS5.42 min, [M+1]⁺ 333.

Example 59

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid1-methyl-piperidin-4-yl ester

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 1-methyl-piperidin-4-ol by the method described in Example 41.Colorless solid (51 mg, 75%). ¹H NMR (CD₃OD) 1.85-1.98 (m, 2H),2.03-2.15 (m, 2H), 2.38 (s, 3H), 2.43 (br q, J=1.3, 3H), 2.40-2.56 (m,2H), 2.73-2.86 (m, 2H), 5.02-5.14 (m, 1H), 7.69 (d, J=4.0, 1H), 7.90 (d,J=4.0, 1H). ¹³C NMR 7.9, 31.4, 46.2, 53.5 (br), 71.9 (br), 116.8 (br),120.3 (q, J=270), 130.7, 135.1, 136.0, 137.5, 159.4, 162.3. ¹⁹F NMR−64.8. LC/MS 4.75 min, [M+1]⁺ 375.

Example 60

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidprop-2-ynylamide

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand propargylamine by the method described in Example 2 Method B. Paleyellow solid (122 mg, 97%). ¹H NMR (DMSO-d₆) 2.41 (d, J=1.3, 3H), 3.25(t, J=2.6, 1H), 4.13 (dd, J=5.7, 2.6, 2H), 7.79 (d, J=4.0, 1H), 7.97 (d,J=4.0, 1H), 9.29 (t, J=5.7, 1H). ¹⁹F NMR −62.30. LC/MS 6.07 min, [M+1]⁺315.

Example 61

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidmethyl-prop-2-ynyl-amide

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand N-methyl propargylamine by the method described in Example 2 methodB. Colorless solid (128 mg, 98%). ¹H NMR (CDCl₃) 2.37 (d, J=1.8, 3H),3.28 (br s, 3H), 4.34 (br s, 2H), 7.48 (d, J=3.5, 1H), 7.51 (br d, 1H).¹⁹F NMR −63.13. LC/MS 6.36 min, [M+1]⁺ 329.

Example 62

(3-Methylaminomethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 3-(tert-butoxycarbonylamino)piperidine (CAS [172603-05-3], CHNTechnologies, Woburn Mass., USA) by the method described in Example 2method B. The intermediate Boc-protected adduct was chromatographed onsilica gel with EtOAc to afford product as a colorless solid (54 mg,44%). LC/MS 7.26 min, [M+1]⁺ 488. The Boc-protected intermediate wasdissolved in 1,4-dioxane (1 mL) and treated with a 4 N solution ofhydrogen chloride in 1,4-dioxane (4 mL) and stirred for 4 hr, afterwhich time the reaction mixture was evaporated to approximately ½ volumeand diluted with ethyl ether (10 mL). The resulting solids were filteredand air dried to afford product as a colorless solid (47 mg, 100%, 44%overall). LC/MS 4.58 min, [M+1]⁺ 388.

Example 63

((R)-3-Amino-pyrrolidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (R)-(+)-3-(Boc-amino)pyrrolidine (CAS [122536-77-0], CHNTechnologies, Woburn Mass., USA) by the method described in Example 2Method B. The intermediate Boc-protected adduct was chromatographed onsilica gel with EtOAc to afford product as a colorless solid (66 mg,30%). LC/MS 6.54 min, [M+1]⁺ 446. The Boc-protected intermediate wasdissolved in 1,4-dioxane (1 mL) and treated with a 4 N solution ofhydrogen chloride in 1,4-dioxane (4 mL) and stirred for 24 hr, afterwhich time the reaction mixture was evaporated to approximately ½ volumeand diluted with ethyl ether (10 mL). The resulting solids were filteredand air dried to afford product as a colorless solid (45 mg, 80%, 24%overall). LC/MS 4.29 min, [M+1]⁺ 346.

Example 64

((S)-3-Amino-pyrrolidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (S)-(−)-3-(Boc-amino)pyrrolidine (CAS [122536-76-9], CHNTechnologies, Woburn Mass., USA) by the method described in Example 2Method B. The intermediate Boc-protected adduct was chromatographed onsilica gel with EtOAc to afford product as a colorless solid (145 mg,65%). LC/MS 6.54 min, [M+1]⁺ 446. The Boc-protected intermediate wasdissolved in 1,4-dioxane (1 mL) and treated with a 4 N solution ofhydrogen chloride in 1,4-dioxane (4 mL) and stirred for 24 hr, afterwhich time the reaction mixture was evaporated to approximately ½ volumeand diluted with ethyl ether (10 mL). The resulting solids were filteredand air dried to afford product as a colorless solid (90 mg, 72%, 47%overall). LC/MS 4.29 min, [M+1]⁺ 346.

Example 65

(S)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]piperidine-3-carboxylicacid ethyl ester

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (S)-(+)-nipecotic acid, ethyl ester (TCI America, Portland Oreg.,USA) by the method described in Example 2 Method B. Colorless solid (415mg, 91%). ¹H NMR (CDCl₃) 1.19 (t, J=7.0, 3H), 1.50-1.60 (m, 1H),1.66-1.82 (m, 2H), 2.02-2.12 (m, 1H), 2.29 (d, J=1.4, 3H), 2.46-2.56 (m,1H), 3.13 (t, J=11.0, 1H), 3.28 (br s, 1H), 4.08 (q, J 7.0, 3H), 4.10(obs m, 1H), 4.34 (br s, 1H), 7.28 (d, J=4.0, 1H), 7.39 (d, J=3.5, 1H).¹⁹F NMR −63.12. LC/MS 6.74 min, [M+1]⁺ 417.

Example 66

(R)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidine-3-carboxylicacid ethyl ester

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (R)-(−)-nipecotic acid, ethyl ester (TCI America, Portland Oreg.,USA) in the same manner as the R isomer. Colorless solid (220 mg, 70%).LC/MS 6.76 min, [M+1]⁺ 417.

Example 67

((S)-3-Dimethylamino-pyrrolidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

A solution of((S)-3-amino-pyrrolidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride (Example 64, 80 mg, 0.21 mmol) in dichloromethane (10 mL)was treated with a 37% aqueous formaldehyde solution (58 μL, 2.10 mmol)followed by sodium triacetoxyborohydride (445 mg, 2.10 mmol). Themixture was stirred for 24 h then quenched with saturated aqueoussolution of NaHCO₃ (10 mL) and stirred for 30 min. The organic portionwas further washed with an additional portion of NaHCO₃ solution (10 mL)followed by a brine solution (10 mL), then dried over MgSO₄, filtered,and evaporated in vacuo to afford product as a colorless solid. ¹H NMR(CDCl₃) 1.70-2.00 (m, 1H), 2.06-2.20 (m, 1 H), 2.23 (s, 6 H), 2.29 (s,3H), 2.62-2.80 (m, 1 H), 3.32-4.00 (m, 4H), 7.42 (d, J=4.0, 1H), 7.47(br d, 1H). LC/MS 4.25 min, [M+1]⁺ 374.

Example 68

((R)-3-Dimethylamino-pyrrolidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from((R)-3-amino-pyrrolidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone,hydrochloride (Example 63, 40 mg, 0.105) in the same manner as the Sisomer. LC/MS 4.27 min, [M+1]⁺ 374.

Example 69

((S)-3-Hydroxymethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonylchloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) and(S)-1-piperidin-3-yl-methanol, hydrochloride (76 mg, 0.5 mmol) by themethod used in Example 46 for the achiral isomer. Gummy solid (70 mg,74%). LC/MS 5.85 min, [M+1]⁺ 375.

Example 70

((R)-3-Hydroxymethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonylchloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) and(S)-1-piperidin-3-yl-methanol, hydrochloride (76 mg, 0.5 mmol) in thesame manner as the S isomer (Example 69). Gummy solid (56 mg, 60%).LC/MS 5.86 min, [M+1]⁺ 375.

Example 71

((R)-3-Dimethylaminomethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

A solution of dimethyl-(S)-1-piperidin-3-ylmethyl-amine, dihydrochloride(Preparative Example 29, 108 mg, 0.5 mmol) in THF/DMF (3 mL/500 μL) wastreated with triethylamine (95 μL, 1.0 mmol) followed by5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonylchloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B). Thereaction mixture was vigorously stirred or 16 h then evaporated anddiluted with water (5 mL). The crude reaction mixture was extracted withEtOAc (2×3 mL) which was then washed with a 1 N NaOH solution (2×3 mL),dried over MgSO₄, filtered, and evaporated in vacuo to afford product asa colorless solid. The solid was dissolved in a EtOAc/hexanes (1:1)mixture (1 mL), filtered through a PTFE syringe filter, and againevaporated in vacuo to afford product as a colorless solid (31 mg, 31%).LC/MS 5.13 min, [M+1]⁺ 402.

Example 72

((S)-3-Dimethylaminomethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from dimethyl-(R)-1-piperidin-3-ylmethyl-amine, dihydrochloride(Preparative Example 28, 108 mg, 0.5 mmol) and5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonylchloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) asdescribed for the R isomer (Example 70). Colorless solid (41 mg, 41%).LC/MS 5.28 min, [M+1]⁺ 402.

Example 73

(S)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]piperidine-3-carboxylicacid amide

A solution of(S)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidine-3-carboxylicacid ethyl ester (Example 65, 88 mg, 0.20 mmol) in 7N methanolic ammonia(5 mL) was heated at 60° C. in a sealed vial for 48 hr. After this timethe reaction mixture was evaporated and triturated and filtered with theaid of water. The filtered solids were air dried to afford product as acolorless solid (67 mg, 86%). LC/MS 5.52 min, [M+1]⁺ 388.

Example 74

(R)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidine-3-carboxylicacid amide

Prepared from(R)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidine-3-carboxylicacid ethyl ester (Example 66, 88 mg, 0.20 mmol) in the same manner asthe S isomer (Example 72). Colorless solid (68 mg, 88%). LC/MS 5.52 min,[M+1]⁺ 388.

Example 75

(3-Methylamino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

A solution of5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonylchloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) in THF (2mL) was treated with a THF solution (2 mL) ofmethyl-piperidin-3-ylmethyl-carbamic acid 9H-fluoren-9-ylmethyl ester,hydrochloride (112 mg, 0.30 mmol, Preparative Example 30) anddiisopropylethylamine (52 μL, 0.30 mmol). The reaction mixture wasallowed to stir for 2 hr then evaporated to ˜1 mL volume and dilutedwith EtOAc (10 mL). The resulting solution was then washed with a 1Naqueous HCl solution (10 mL), then a saturated aqueous solution ofNaHCO₃ (10 mL) followed by a brine solution (10 mL). The organic portionwas then dried over MgSO₄, filtered, and evaporated in vacuo to affordcrude oil. The oil was chromatographed on silica gel with EtOAc/hexane(75%) to afford the Fmoc-protected intermediate as a colorless oil (103mg, 69%). LC/MS 7.63 min, [M+1]⁺ 596. The intermediate was thendissolved in DMF (2.5 mL), treated with morpholine (200 μL), and stirredfor 4 h resulting in precipitated colorless solids. The reaction mixturewas cooled to 0° C. and filtered through a glass wool plug to removesolids, then evaporated in vacuo to afford crude product which waschromatographed on a small silica gel column with EtOAc then MeOH/EtOAc(10%) containing 2% triethylamine to afford product as a copper coloredoil (59 mg, 89%, 61% overall). ¹H NMR (CDCl₃) 1.54-1.64 (m, 2H),1.84-1.92 (m, 1 H), 2.05-2.14 (m, 1H), 2.37 (d, J=1.8, 3H), 2.51 (br s,3 H), 2.70-2.80 (m, 1 H), 3.13 (dd, J=13.2, 9.2, 1H), 3.22-3.30 (m, 1H),4.10 (br, 1H), 4.34 (br d, J=11.0, 1H), 5.05 (br s, 1H), 7.37 (d, J=4.0,1H), 7.46 (d, J=4.0, 1H). ¹⁹F NMR −63.11. LC/MS 4.46 min, [M+1]⁺ 374.

Example 76

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acidcyclohexylamide

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand cyclohexylamine by the method described in Example 2 Method Breversing the order of addition such that intermediate solid acidchloride was added to a THF solution of triethylamine and piperidinederivative. Colorless solid (80 mg, 89%). ¹H NMR (CDCl₃) 1.18-1.36 (m,1H), 1.36-1.50 (m, 1H), 1.60-1.82 (m, 4H), 1.98-2.10 (m, 2H), 2.37 (d,J=0.9, 3H), 3.90-4.04 (m, 1H), 5.88 (br d, J=7.0, 1H), 7.49 (d, J=4.0,1H), 7.51 (d, J=3.5, 1H). ¹⁹F NMR −63.36. LC/MS 7.18 min, [M+1]⁺ 359.

Example 77

(S)-5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylicacid (1-aza-bicyclo[2.2.2]oct-3-yl)-amide

A suspension of (S)-(−)-aminoquinuclidine dihydrochloride (55 mg, 0.275mmol) in dichloromethane (1 mL) as treated with triethylamine (53 μL,0.55 mmol) followed by5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonylchloride (74 mg, 0.25 mmol) and the reaction mixture allowed to stir for20 hr. After this time, the reaction mixture was evaporated and theresidue partitioned between EtOAc (5 mL) and a 1 N HCl solution (10 mL).The aqueous portion was then basified to pH ˜10-12 with a 1N NaOHsolution. The aqueous portion was then extracted with EtOAc (10 mL)which was then washed with a brine solution (10 mL), dried over MgSO₄,filtered, and evaporated in vacuo to afford product as a colorless solid(38 mg, 40%). ¹H NMR (CDCl₃) 1.50-1.62 (m, 1H), 1.70-1.88 (m, 3H),2.08-2.12 (m, 2H), 2.37 (d, J=1.3, 3H), 2.72-3.10 (m, 5H), 3.44 (ddd,J=14.0, 9.7, 2.2, 1H), 4.14-4.22 (m, 1H), 6.56 (br d, J=7.0, 1H), 7.49(d, J=4.0, 1H), 7.56 (d, J=4.0, 1H). ¹⁹F NMR −63.13. LC/MS 4.63 min,[M+1]⁺ 386.

Example 78

(R)-5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylicacid (1-aza-bicyclo[2.2.2]oct-3-yl)-amide

Prepared from (R)-(+)-aminoquinuclidine dihydrochloride in the samemanner as the R isomer (Example 77). Colorless solid (40 mg, 42%). LC/MS4.58 min, [M+1]⁺ 386.

Example 79

(4-Fluoro-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-fluoromethylpiperidine hydrochloride by the method described inExample 41. Colorless solid (116 mg, 89%). ¹H NMR (CDCl₃) 1.85-2.03 (m,4H), 2.37 (s, 3H), 3.63-3.76 (m, br, 2H), 3.89-4.03 (m, br, 2H), 4.95(dm, J_(H-F)=48, 1H), 7.34 (d, J=3.6, 1H), 7.46 (d, J=3.6, 1H). ¹³C NMR7.7, 31.3 (J=20), 41.2 (br), 87.2 (d, J=171), 114.5 (q, J=2), 118.3 (q,J=271), 127.8, 129.0, 131.1, 139.6, 155.0 (q, J=40), 157.7, 162.6. ¹⁹FNMR −63.1. LC/MS 6.42 min, [M+1]⁺ 363.

Example 80

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-(3-trifluoromethyl-piperidin-1-yl)-methanone

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (±)-3-trifluoromethylpiperidine hydrochloride by the methoddescribed in Example 41. Colorless solid (123 mg, 82%). ¹H NMR (CDCl₃)1.53-1.76 (m, br, 2H), 1.84-1.95 (m, br, 1H), 2.10-2.22 (m, br, 1H),2.31-2.43 (m, br, 4H), 2.92-3.16 (m, br, 2H), 4.28-4.45 (m, br, 1H),4.54-4.72 (m, br, 1H), 7.34 (d, J=4.0, 1H), 7.47 (d, J=4.0, 1H). ¹³C NMR7.7, 23.5, 24.2, 40.5 (q, J=27), 44.0 (br), 46.3 (br), 114.5 (q, J=2),118.5 (q, J=271), 126.1 (q, J=283), 127.8, 129.1, 131.4, 139.3, 155.0(q, J=41), 157.6, 162.8. ¹⁹F NMR −72.8, −63.2. LC/MS 6.99 min, [M+1]⁺413.

Example 81

(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone

Prepared from5-(5-trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 4-trifluoromethylpiperidine hydrochloride by the method described inExample 41. Colorless solid (135 mg, 90%). ¹H NMR (CDCl₃) 1.54-1.73 (m,br, 2H), 2.00 (d, br, J=12.7, 2H), 2.31-2.42 (m, br, 4H), 2.89-3.12 (m,br, 2H), 4.43-4.68 (m, br, 2H), 7.33-7.37 (m, br, 1H), 7.44-7.50 (m, br,1H). ¹³C NMR 7.7, 24.7, 40.5 (q, J=28), 44.4 (br), 114.5 118.5 (q,J=271), 126.8 (q, J=278), 127.8, 129.1, 131.3, 139.4, 155.0 (q, J=41),157.6, 162.6. ¹⁹F NMR −74.2, −63.2. LC/MS 7.01 min, [M+1]⁺ 413.

Example 82

6-Dihydro-2H-pyridin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(5-trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand 1,2,3,6-tetrahydropyridine hydrochloride by the method described inExample 41. Colorless solid (59 mg, 89%). ¹H NMR (CDCl₃) 2.26-2.34 (m,br, 2H), 2.36 (s, 3H), 3.81 (t, br, J=5.9, 2H), 4.20-4.25 (m, br, 2H),5.67-5.77 (m, 1H), 5.88-5.97 (m, 1H), 7.37 (d, J=3.9, 1H), 7.47 (d,J=3.9, 1H). ¹³C NMR 7.7, 25.5 (br), 29.7, 44.5 (br), 114.5 (q, J=2),118.5 (q, J=271), 123.8, 125.7, 127.8, 128.9, 131.1, 140.3, 155.0 (q,J=41), 157.7, 162.7. ¹⁹F NMR −63.1. LC/MS 6.61 min, [M+1]⁺ 343.

Example 83

(3-Hydroxy-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

Prepared from5-(5-trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (±)-3-hydroxypiperidine hydrochloride by the method described inExample 41. Colorless solid (101 mg, 85%). ¹H NMR (CD₃OD) 1.51-1.71 (m,2H), 1.84-2.05 (m, 2H), 2.39 (q, J_(H-F)=1.5, 3H), 3.34-3.65 (m, 2H),3.68-3.85 (m, 2H), 3.86-4.14 (m, 1H), 7.49 (d, br, J=3.9, 1H), 7.60 (d,br, J=3.9, 1H). ¹³C NMR 8.0, 23.6 (br), 33.5, 45.1 (br), 55.1 (br),67.0, 116.7 (q, J=2), 120.3 (q, J=270), 129.8, 130.9, 132.4, 141.1,155.8 (q, J=40), 159.4, 165.0. ¹⁹F NMR −64.8. LC/MS 6.00 min, [M+1]⁺361.

Example 84

(±)((cis)-3,4-Dihydroxy-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

A solution of(3,6-Dihydro-2H-pyridin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone(31 mg, 0.09 mmol) in acetone (2 mL) and water (1 mL) was treated withN-methylmorpholine-N-oxide (17 mg, 0.14 mmol) followed by K₂OsO₄.2H₂O(catalytic). The resulting mixture was stirred at room temperature for16 hr, at which time LC/MS analysis showed full conversion of startingmaterial (6.91 min, MH⁺=343) to product (5.57 min, MH⁺=377).

A saturated aqueous Na₂SO₃ solution (10 mL) was then added and thereaction stirred vigorously for 10 minutes. The mixture was thenpartitioned between CH₂Cl₂ (10 mL) and water (10 mL) and the aqueousportion further extracted with CH₂Cl₂ (3×20 mL). The combined organicextract was dried over Na₂SO₄, filtered, and concentrated in vacuo tocrude product (32 mg).

Gradient column chromatography on silica eluting with 75% EtOAc/hexanes,100% EtOAc, 5% then 10% MeOH/EtOAc gave the title compound as acolorless solid (29 mg, 0.77 mmol, 85%). ¹H NMR (CD₃OD) 1.69-1.81 (m,1H), 1.85-1.99 (m, 1H), 2.39 (s, 3H), 3.37-3.72 (m, br, 2H), 3.75-3.84(m, 1H), 3.84-4.16 (m, br, 3H), 7.53 (s, br, 1H), 7.60 (d, br, J=3.8,1H). ¹³C NMR 8.0, 30.9 (br), 41.6 (br), 52.1 (br), 69.5, 70.0, 116.7 (q,J=2), 120.3 (q, J=270), 129.8, 131.1, 132.4, 141.1, 155.8 (q, J=40),159.4, 165.3. ¹⁹F NMR −64.8. LC/MS 5.57 min, [M+1]⁺ 377.

Example 85

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-(7-oxa-3-aza-bicyclo[4.1.0]hept-3-yl)-methanone

A solution of(3,6-Dihydro-2H-pyridin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone(177 mg, 0.52 mmol) in CH₂Cl₂ (5 mL) was treated with MCPBA (presumed50% purity, 356 mg, 1.03 mmol). The reaction was stirred at roomtemperature for 16 hr at which time LC/MS analysis showed fullconversion of starting material (6.93 min, MH⁺=343) to product (6.29min, MH⁺=359).

The reaction mixture was then treated with a 5% NaOH solution (10 mL)with vigorous mixing. The mixture was partitioned between CH₂Cl₂ (10 mL)and water (10 mL) and the aqueous portion further extracted with CH₂Cl₂(3×20 mL). The combined organic extract was dried over Na₂SO₄, filtered,and concentrated in vacuo to afford crude product (192 mg).

Gradient column chromatography on silica eluting with 75% EtOAc/hexanes,100% EtOAc then 10% MeOH/EtOAc gave the title compound as a colorlesssolid (177 mg, 0.49 mmol, 95%). ¹H NMR (CDCl₃) 1.98-2.26 (m, br, 2H),2.34 (s, br, 3H), 3.18-3.73 (m, br, 4H), 3.82-4.30 (m, br, 2H), 7.33 (s,br, 1H), 7.43 (s, br, 1H). ¹³C NMR 7.6, 24.6 (br), 37.1-47.2 (br), 50.1,50.5, 114.5 (br), 118.4 (q, J=271), 127.8, 129.2, 131.2, 139.5, 154.9(q, J=40), 157.6, 162.9. ¹⁹F NMR −63.2. LC/MS 6.29 min, [M+1]⁺ 359.

Example 86

(±)((trans)-3,4-Dihydroxy-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

A solution of[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-(7-oxa-3-aza-bicyclo[4.1.0]hept-3-yl)-methanone(93 mg, 0.26 mmol) in CH₃CN (4 mL) and H₂O (2 mL) was treated withcerium (IV) ammonium nitrate (cat.). The resulting solution was stirredat room temperature for 40 hr, at which time LC/MS analysis confirmedfull conversion of starting material (6.29 min, MH⁺=359) to product(5.53 mins, MH⁺=377).

The mixture was then partitioned between CH₂Cl₂ (10 mL) and water (10mL) and aqueous portion further extracted with CH₂Cl₂ (3×20 mL), driedover Na₂SO₄, filtered, and concentrated in vacuo to afford crudeproduct.

Gradient column chromatography on silica eluting with 100% EtOAc, then5% MeOH/EtOAc gave the title compound as a colorless solid (72 mg, 0.19mmol, 73%). ¹H NMR (CD₃OD) 1.48-1.63 (m, br, 1H), 1.99-2.14 (m, br, 1H),2.39 (s, br, 3H), 3.32-3.72 (m, br, 4H), 3.87-4.19 (m, br, 2H), 7.50 (s,br, 1H), 7.59 (s, br, 1H). ¹³C NMR 8.0, 30.3-33.0 (br), 40.5-43.8 (br),71.7, 72.1 (br), 116.6 (br), 120.2 (q, J=270), 129.8, 131.0, 132.5,140.8, 155.8 (q, J=41), 159.3, 164.9. ¹⁹F NMR −64.7. LC/MS 5.53 min,[M+1]⁺ 377.

Example 87

(3R,4S)-1-({5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}carbonyl)piperidine-3,4-diol

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (3R,4S)-3,4-Piperidinediol (CAS [135501-61-0]) by the methoddescribed in Example 2 Method B reversing the order of addition suchthat solid acid chloride was added to a THF/DMF (4 mL/1 mL) solution oftriethylamine and (3R,4S)-3,4-Piperidinediol (2 mmol). After 30 min thereaction mixture was quenched with the addition of water. The resultingsolids were then filtered and washed with a 1 N aqueous HCl solutionfollowed by water. The material was air dried to afford product as acolorless solid (304 mg, 81%). ¹H NMR (DMSO-d6) 1.53-1.60 (m, 1 H),1.65-1.71 (m, 1 H), 2.34 (d, J=1.3, 3 H), 3.10-4.00 (br m, 6 H), 4.70(d, J=4.4, 1 H), 4.81 (d, J=4.0, 1 H), 7.54 (br s, 1 H), 7.65 (d, J=4.0,1 H). ¹⁹F NMR −62.2. LC/MS 5.44 min, [M+1]⁺ 377.

Example 88

(3S,4R)-1-({5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}carbonyl)piperidine-3,4-diol

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (3S,4R)-3,4-Piperidinediol (CAS [868051-84-7]) in the same manner asthe (3R,4S) isomer (Example 87) to afford product as a colorless solid(303 mg, 81%). LC/MS 5.43 min, [M+1]⁺ 377.

Example 89

(3R)—N-methyl-1-({5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}carbonyl)piperidine-3-carboxamide

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (3R)—N-methylpiperidine-3-carboxamide (Preparative Example 31) bythe method described in Example 2 Method B reversing the order ofaddition such that solid acid chloride was added to a THF solution oftriethylamine and (3R)—N-methylpiperidine-3-carboxamide. After 3 hr thereaction mixture was evaporated in vacuo and filtered with the aid ofwater. The resulting solids were then washed with a 1 N aqueous HClsolution followed by water. The material was air dried to afford productas a colorless solid (157 mg, 86%). LC/MS 6.00 min, [M+1]⁺ 402.

Example 90

(3S)—N-methyl-1-({5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}carbonyl)piperidine-3-carboxamide

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (3S)—N-methylpiperidine-3-carboxamide (Preparative Example 32) inthe same manner as the 3R isomer (Example 89) to afford product as acolorless solid (303 mg, 81%). LC/MS 5.88 min, [M+1]⁺ 402.

Example 91

N-methyl-N-{[(3S)-1-({5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}carbonyl)piperidin-3-yl]methyl}amine,hydrochloride

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand tert-butyl methyl[(3R)-piperidin-3-ylmethyl]carbamate (PreparativeExample 33, 298 mg, 1.30 mmol) by the method described in Example 2Method B reversing the order of addition such that solid acid chloride(0.90 eq) was added to a THF solution of triethylamine and tert-butylmethyl[(3R)-piperidin-3-ylmethyl]carbamate. The reaction was allowed tostir 4 hr then partitioned between EtOAc (10 mL) and a 1 N aqueous HClsolution (10 mL). The organic portion was washed with a further portionof 1N HCl solution (10 mL) followed by a saturated aqueous NaHCO₃solution (10 mL) and brine (10 mL). The organic layer was then driedover MgSO₄, filtered, and evaporated to a residue that waschromatographed on silica gel with EtOAc/hexane (40% then 60%) as eluantto afford Boc-protected intermediate as a yellow-tinted oil (423 mg,67%). LC/MS 7.44 min, [M+1]⁺ 487. The intermediate was then treated witha 4 N solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirredfor 24 hr, after which time the reaction mixture was evaporated in vacuoto afford a free-flowing colorless powder (320 mg, 88%). LC/MS 4.91 min,[M+1]⁺ 388.

Example 92

N-methyl-N-{[(3R)-1-({5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}carbonyl)piperidin-3-yl]methyl}amine,hydrochloride

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand tert-butyl methyl[(3S)-piperidin-3-ylmethyl]carbamate (PreparativeExample 34, 340 mg, 1.48 mmol) in the same manner as the 3S isomer(Example 91) to afford Boc-protected intermediate as a colorless oil(547 mg, 76%). LC/MS 7.36 min, [M+1]⁺ 487. The product was obtained as acolorless free-flowing powder (440 mg, 93%). LC/MS 4.82 min, [M+1]⁺ 388.

Example 93

(3R)—N-methyl-1-({5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}carbonyl)piperidin-3-amine,hydrochloride

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand (tert-butyl methyl[(3R)-piperidin-3-yl]carbamate (PreparativeExample 35, presumed quantitative yield, 4.48 mmol) by the methoddescribed in Example 2 Method B reversing the order of addition suchthat solid acid chloride (0.90 eq) was added to a THF solution oftriethylamine and (tert-butyl methyl[(3R)-piperidin-3-yl]carbamate(presumed quantitative yield, 4.48 mmol). The reaction was allowed tostir 4 hr, evaporated in vacuo, and the solids filtered with the aid ofwater. The air-dried solids were then chromatographed on a short silicagel column with EtOAc/hexane (75%) to afford Boc-protected intermediateas a colorless solid (1.61 g, 76%). LC/MS 7.33 min, [M+1]⁺ 474. Theintermediate was then treated with a 4 N solution of hydrogen chloridein 1,4-dioxane (20 mL) and stirred for 24 hr, after which time thereaction mixture was evaporated in vacuo to afford a free-flowingcolorless powder (1.14 g, 82%, some loss of material had occurred onrotary evaporation). LC/MS 4.57 min, [M+1]⁺ 374.

Example 94

(3S)—N-methyl-1-({5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}carbonyl)piperidin-3-amine,hydrochloride

Prepared from5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acidand tert-butyl methyl[(3S)-piperidin-3-ylmethyl]carbamate (PreparativeExample 36, presumed quantitative yield, 4.48 mmol) in the same manneras the 3R isomer (Example 93) to afford Boc-protected intermediate as acolorless oil (1.51 g, 71%). LC/MS 7.32 min, [M+1]⁺ 474. The product wasobtained as a colorless free-flowing powder (1.06 g, 81%, some loss ofmaterial had occurred on rotary evaporation). LC/MS 4.55 min, [M+1]⁺374.

Example 95

(2-methoxyphenyl){5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}methanone

Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and2-methoxybenzoyl chloride by the method described in Example 3. Crudeproduct was chromatographed on silica gel with EtOAc/hexanes (15 then25%) as eluant to afford product as a yellow-tinted oil (100 mg, 54%).¹H NMR (CDCl₃) 2.39 (d, J=1.3, 3 H), 3.82 (s, 3 H), 7.01-7.08 (m, 2 H),7.27-7.54 (m, 4 H). ¹³C NMR 8.0, 55.9, 111.9, 115.9 (q, J=151), 120.7,128.2, 129.0, 129.6, 132.7, 135.0, 136.3, 147.1, 155.4 (q, J=41), 157.3,158.0, 188.2. ¹⁹F NMR −63.1. LC/MS 7.50 min, [M+1]⁺ 368.

Example 96

1-{5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}ethanone

Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and2-acetoxybenzoyl chloride by the method described in Example 3. Crudeproduct was chromatographed on silica gel with EtOAc/hexanes (15 then25%) as eluant to afford product as a tan colored solid (80 mg, 58%). ¹HNMR (CDCl₃) 2.39 (d, J=1.3, 3 H), 3.62 (s, 3 H), 7.57 (d, J=4.0, 1 H),7.74 (d, J=4.0, 1 H). ¹⁹F NMR −63.1. LC/MS 7.82 min, [M+1]⁺ 276.

Example 97

(2-hydroxyphenyl){5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}methanone

A solution of(2-methoxyphenyl){5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}methanone(Example 95, 37 mg, 0.1 mmol) in dichloromethane (2 mL) at −78° C. wastreated with boron tribromide (100 μL of a 1 M dichloromethane solution,0.1 mol) and allowed to warm to 0° C. and stir at that temperature for16 h. After that time the reaction was quenched with water (3 mL) andpartitioned between water (10 mL) and EtOAc (10 mL). The organic extractwas washed with a brine solution (10 mL) then dried over Na₂SO₄,filtered, and concentrated in vacuo to afford crude product. The crudeproduct was chromatographed on silica gel with EtOAc/hexanes (20%) aseluant to afford product as a yellow colored solid (29 mg, 82%). ¹H NMR(CDCl₃) 2.92 (d, J=1.8, 3 H), 7.46-7.76 (m, 2 H), 8.03-8.08 (m, 1 H),8.12 (d, J=4.0, 1 H), 8.28 (d, J=4.0, 1 H), 8.46 (dd, J=8.4, 1.8, 1 H),11.50 (s, 1 H). ¹⁹F NMR −63.1.

What is claimed is:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is(C₁-C₆)alkyl substituted with one or more R_(h); each R_(h) isindependently selected from the group consisting of fluoro, bromo, iodo,cyano, and nitro; A¹ is CR²; A² and A³ are each independently O (oxygen)or N (nitrogen) with the proviso that when A² is O (oxygen), A³ is N(nitrogen) and when A² is N (nitrogen), A³ is O (oxygen); R² is H(hydrogen), (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or aryl optionally substituted with one or more halo; Bis aryl or heteroaryl, each optionally substituted with one or more R³;each R³ is independently (C₁-C₆)alkyl, or aryl(C₁-C₆)alkyl; X is —C(═O)—or —C(═S)— each n is independently an integer selected from 0, 1, and 2;each z is independently an integer selected from 1, and 2; Y is —N(R⁴)₂;the two R⁴ groups are taken together with the nitrogen to which they areattached to form a 3-8 membered monocyclic or a 7-12 membered bicyclicring system, each optionally comprising one or more additionalheteroatom groups selected from O (oxygen), S(O)_(z), and NR_(c) whereineach ring system is optionally substituted with one or more R_(d); eachR_(c) is independently selected from the group consisting of hydrogen,(C₁-C₆) alkyl, aryl, heteroaryl, (C₁-C₆)alkylsulfonyl, arylsulfonyl,(C₁-C₆)alkylC(O)—, arylC(O)—, hydroxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl,heterocycle, (C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylaminocarbonyl, andarylaminocarbonyl; each R_(d) is independently halo, cyano, nitro, oxo,R_(f)R_(g)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(f)R_(g), —C(O)NR_(f)R_(g),—NR_(e)C(O)R_(g), arylC(O)NR_(f)R_(g), —C(O)OH, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, —(CH₂)_(n)OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₁-C₆)alkylC(O)—, (C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylC(O)O—, heterocycle,aryl, heterocycle(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl, —NR_(e)S (O)_(z)aryl, —NR_(e)C(O)NR_(f)R_(g),—NR_(e)C(O)OR_(f), or —OC(O)NR_(f)R_(g); each R_(e) is independentlyhydrogen, (C₁-C₆)alkyl, aryl or heteroaryl; each R_(f) and R_(g) isindependently hydrogen, (C₁-C₆)alkyl, aryl or heteroaryl, or R_(f) andR_(g) are optionally taken together with the nitrogen to which they areattached to form a 3-8 membered monocyclic or a 7-12 membered bicyclicring system, each optionally comprising one or more additionalheteroatom groups selected from O (oxygen), S(O)_(z), and NR_(c) whereineach ring system is optionally substituted with one or more R_(q); eachR_(q) is independently halo, cyano, nitro, oxo, —NR_(i)R_(j),R_(i)R_(j)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(i)R_(j), —C(O)NR_(i)R_(j),—NR_(k)C(O)R_(j), arylC(O)NR_(i)R_(j), —C(O)OH, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, —(CH₂)_(n)OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₁-C₆)alkylC(O)—, (C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylC(O)O—, heterocycle,aryl, heterocycle(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,—NR_(e)S(O)_(z)(C₁-C₆)alkyl, —NR_(k)S(O)_(z)aryl,—NR_(k)C(O)NR_(i)R_(j), —NR_(k)C(O)OR_(i), or —OC(O)NR_(i)R_(j); eachR_(k) is independently hydrogen, (C₁-C₆)alkyl, aryl or heteroaryl; eachR_(i) and R_(j) is independently hydrogen, (C₁-C₆)alkyl, aryl orheteroaryl; and the dashed line represents an optional double bondwherein the ring comprising A¹, A², and A³ is heteroaromatic.
 2. Thecompound of claim 1, wherein B is heteroaryl optionally substituted withone or more R³.
 3. The compound of claim 2 having the formula:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim2 having the formula:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim2 having the formula:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim5, wherein X is —C(═O)—.
 7. A compound of the Formula Ie:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is(C₁-C₆)alkyl substituted with one or more R_(h); each R_(h) isindependently selected from the group consisting of fluoro, bromo, iodo,cyano, and nitro; A^(l) is CR²; R² is H (hydrogen), (C₁-C₆)alkyl,aryl(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or aryl optionallysubstituted with one or more halo; A² and A³ are each independentlyO(oxygen) or N (nitrogen) with the proviso that when A² is O(oxygen), A³is N (nitrogen) and when A² is N (nitrogen), A³ is 0 (oxygen); Z¹ is N(nitrogen), or CR⁵; Z² is N (nitrogen), or CR⁵; Z³ is N (nitrogen), orCR⁵; Z⁴ is N (nitrogen), or CR⁵; each R⁵ is independently H (hydrogen),(C₁-C₆)alkyl, —NR_(i)R_(j), —C(O)NR_(i)R_(j), or aryl(C₁-C₆)alkyl; X is—C(═O)—or —C(═S)—; Y is —N(R⁴)₂, —OR⁴, —SR⁴, or —C(R⁴)₃, each optionallysubstituted with one or more R_(d); each R⁴ is independently selectedfrom the group consisting of hydrogen, —OH, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl,(C₃-C₈)cycloalkyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl, heteroaryl, aryl,aryl(C₁-C₆)alkyl, heterocycle, heterocycle(C₁-C₆)alkyl,heterocycle(C₁-C₆)alkanoyl and NR_(a)R_(b); or when Y is —N(R⁴)₂, thentwo R⁴ groups are optionally taken together with the nitrogen to whichthey are attached to form a 3-8 membered monocyclic or a 7-12 memberedbicyclic ring system, each optionally comprising one or more additionalheteroatom groups selected from O(oxygen), S(O)_(z), and NR_(c) whereineach ring system is optionally substituted with one or more R_(d); eachR_(a) and R_(b) is independently hydrogen or (C₁-C₆)alkyl, or R_(a) andR_(b) are optionally taken together with the nitrogen to which they areattached to form a 3-8 membered monocyclic or a 7-12 membered bicyclicring system, each optionally substituted with one or more C₁-C₆alkylgroups; each R_(c) is independently selected from the group consistingof hydrogen, (C₁C₆)alkyl, aryl, heteroaryl, (C₁C₆)alkylsulfonyl, arylsulfonyl, (C₁-C₆)alkylC(O)—, arylC(O)—, hydroxy(C₁-C₆)alkyl,alkoxy(C₁-C₆)alkyl, heterocycle, (C₁-C₆)alkylOC(O)—,(C₁-C₆)alkylaminocarbonyl, and arylaminocarbonyl; each R_(d) isindependently halo, cyano, nitro, oxo, R_(f)R_(g)N(C₁-C₆)alkyl,—CH₂)_(n)NR_(f)R_(g), —C(O)NR_(f)R_(g), —NR_(e)C(O)R_(g),arylC(O)NR_(f)R_(g), —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,—(CH₂)_(n)OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)alkylC(O)—,(C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylC(O)O—, heterocycle, aryl,heterocycle(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —NR,S (O)_(z)(C₁-C₆)alkyl,—NR_(e),S(O)_(z)aryl, —NR_(e)C(O)NR_(f)R_(g), —NR_(e)C(O)OR_(f), or—OC(O)NR_(f)R_(g); each n is independently an integer selected from 0,1, and 2; each z is independently an integer selected from 0, 1, and 2;each R_(e) is independently hydrogen, (C₁-C₆)alkyl, aryl or heteroaryl;each R_(f) and R_(g) is independently hydrogen, (C₁-C₆)alkyl, aryl orheteroaryl, or R_(f) and R_(g) are optionally taken together with thenitrogen to which they are attached to form a 3-8 membered monocyclic ora 7-12 membered bicyclic ring system, each optionally comprising one ormore additional heteroatom groups selected from O(oxygen), S(O_(z), andNR_(c) wherein each ring system is optionally substituted with one ormore R_(q); each R_(q) is independently halo, cyano, nitro, oxo,R_(i)R_(j)N(C₁-C₆)alkyl, —CH₂)_(n)NR_(i)R_(j), —C(O)NR_(i)R_(j),—NR_(k)C(O)R_(j), arylC(O)NR_(i)R_(j), —C(O)OH, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, —(CH₂),OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₁-C₆)alkylC(O)—, (C₁-C₆)alkylOC(O)—, (C₁C₆)alkylC(O)O—, heterocycle,aryl, heterocycle(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —NR_(e),S (O)_(z)(C₁-C₆)alkyl, —NR_(k)S (O),aryl, —NR_(k)C(O)NR_(i)R_(j),—NR_(k)C(O)OR_(i), or —OC(O)NR_(i)R_(j); each R_(k) is independentlyhydrogen, (C₁-C₆)alkyl, aryl or heteroaryl; each R_(i) and R_(i) isindependently hydrogen, (C₁-C₆)alkyl, aryl or heteroaryl; and the dashedline represents an optional double bond wherein the ring comprising A¹,A², and A³ is heteroaromatic and the ring comprising Z¹, Z², Z³ and Z⁴is aromatic or heteroaromatic.
 8. The compound of claim 7 having theformula:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim7 selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim7 having the formula:

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim10, wherein R¹is CF₃ and A^(l)is CR².
 12. The compound of claim 7 havingthe formula:

or a pharmaceutically acceptable salt thereof.
 13. A compound of formulaI:

or a pharmaceutically acceptable salt thereof, wherein: R¹is(C₁-C₆)alkyl substituted with one or more R_(h); each R_(h) isindependently selected from the group consisting of fluoro, iodo, bromo,cyano, and nitro; A^(l) is CR²; A² and A³ are each independentlyO(oxygen) or N (nitrogen) with the proviso that when A² is O(oxygen), A³is N (nitrogen) and when A² is N (nitrogen), A³ is O (oxygen); R² is H(hydrogen), (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or aryl optionally substituted with one or more halo; Bis aryl or heteroaryl, each optionally substituted with one or more R³;each R³ is independently (C₁—C₆)alkyl, or aryl(C₁—C₆)alkyl; X is —C(═O)—or —C(═S)—; each n is independently an integer selected from 0, 1, and2; each z is independently an integer selected from 1, and 2; Y is R⁴,—SR⁴, or —C(R⁴)₃, each optionally substituted with one or more R_(d);each R⁴ is independently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkanoyl,(C₁—C₆)alkoxycarbonyl, (C₃-C₈)cycloalkyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,heteroaryl, aryl, aryl(C₁-C₆)alkyl, heterocycle,heterocycle(C₁-C₆)alkyl, heterocycle(C₁-C₆)alkanoyl, and NR_(a)R_(b);each R_(a) and R_(b) is independently (C₁-C₆)alkyl, or R_(a) and R_(b)are optionally taken together with the nitrogen to which they areattached to form a 3-8 membered monocyclic or a 7-12 membered bicyclicring system, each optionally substituted with one or more C₁-C ₆alkylgroups; each R_(c) is independently selected from the group consistingof hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₁-C₆)alkylsulfonyl,arylsulfonyl, (C₁-C₆)alkylC(O)—, arylC(O)—, hydroxy(C₁-C₆)alkyl,alkoxy(C₁-C₆)alkyl, heterocycle, (C₁-C₆)alkylOC(O)—,(C₁-C₆)alkylaminocarbonyl, and arylaminocarbonyl; each R_(d) isindependently chloro, bromo, iodo, cyano, nitro, oxo,R_(f)R_(g)N(C₁-C₆)alkyl, —C(O)NR_(f)R_(g), —NR_(e)C(O)R_(g),arylC(O)NR_(f)R_(g), —C(O)OH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,—(CH₂)_(n)OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₁-C₆)alkylC(O)—,(C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylC(O)O—, heterocycle, aryl,heterocycle(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —NR_(e),S(O)_(z)(C₁-C₆)alkyl, —NR_(e)S(O)_(z)aryl, —NR_(e)C(O)NR_(f)R_(g),—NR_(e)C(O)OR_(f), or —OC(O)NR_(f)R_(g); each R_(e) is independentlyhydrogen, (C₁-C₆)alkyl, aryl or heteroaryl; each R_(f) and R_(g) isindependently hydrogen, (C₁-C₆)alkyl, aryl or heteroaryl, or R_(f) andR_(g) are optionally taken together with the nitrogen to which they areattached to form a 3-8 membered monocyclic or a 7-12 membered bicyclicring system, each optionally comprising one or more additionalheteroatom groups selected from O(oxygen), S(O)_(z)and NR_(c)whereineach ring system is optionally substituted with one or more R_(q); eachR_(q) is independently halo, cyano, nitro, oxo, —NR_(i)R_(j),R_(i)R_(j)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(i)R_(j), —C(O)NR_(i)R_(j),—NR_(k)C(O)R_(j), arylC(O)NR_(i)R_(j), —C(O)OH, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, —(CH₂)_(nOH, (C) ₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₁-C₆)alkylC(O)—, (C₁-C₆)alkylOC(O)—, (C₁—C₆)alkylC(O)O—, heterocycle,aryl, heterocycle(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —NR_(e),S(O)_(z)(C₁-C₆)alkyl, —NR_(k)S (O)_(z),aryl, —NR_(k)C(O)NR_(i)R_(j),—NR_(k)C(O)OR_(i), or —OC(O)NR_(i)R_(j); each R_(k) is independentlyhydrogen, (C₁-C₆)alkyl, aryl or heteroaryl; each R_(i) and R_(j) isindependently hydrogen, (C₁-C₆)alkyl, aryl or heteroaryl; and the dashedline represents an optional double bond wherein the ring comprising A¹,A², and A³ is heteroaromatic.
 14. The compound of claim 13, wherein X is—C(═O)—.
 15. The compound of claim 13 having the formula:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim13 having the formula:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim13 having the structure of formula Id:

or a pharmaceutically acceptable salt thereof, wherein: Z¹ is S(sulfur), and Z² Z³ are each independently CR⁵; each R⁵ is independentlyH (hydrogen), (C₁-C₆)alkyl, —NR_(i)R_(j), —C(O)NR_(i)R_(j), oraryl(C₁-C₆)alkyl; each R_(i) and R_(j) is independently hydrogen,(C₁-C₆)alkyl, aryl or heteroaryl; and the dashed line represents anoptional double bond wherein the ring comprising Z¹, Z², and Z³ isheteroaromatic.
 18. The compound of claim 17 having the formula:

or a pharmaceutically acceptable salt thereof.
 19. The compound of claim17 having the formula:

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim13, wherein B is heteroaryl optionally substituted with one or more R₃.21. A pharmaceutical composition comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom the group consisting of aryl and (C₁-C₆)alkyl, each optionallysubstituted with one or more R_(h); each R_(h) is independently selectedfrom the group consisting of halo, cyano, nitro, and —OH; A^(l) is CR²;A² and A³ are each independently O(oxygen) or N (nitrogen) with theproviso that when A² is O(oxygen), A³ is N (nitrogen) and when A² is N(nitrogen), A³ is O (oxygen); R² is H (hydrogen), (C₁-C₆)alkyl,aryl(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or aryl optionallysubstituted with one or more halo; B is aryl or heteroaryl, eachoptionally substituted with one or more R³; each R³ is independently(C₁-C₆)alkyl, or aryl(C₁-C₆)alkyl; X is —C(═O)—, —C(═S)—, —C(R⁴)₂—,—S(O)— or —S—; each n is independently an integer selected from 0, 1,and 2; each z is independently an integer selected from 1, and 2; Y isR⁴, —N(R⁴)₂, —OR⁴, —SR⁴, or —C(R⁴)₃, each optionally substituted withone or more R_(d); each R⁴ is independently selected from the groupconsisting of —OH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, (C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₃-C₈)cycloalkyl, heteroaryl, aryl, aryl(C₁-C₆)alkyl,heterocycle, heterocycle(C₁-C₆)alkyl, and heterocycle(C₁-C₆)alkanoyl; orwhen Y is —N(R⁴)₂, then two R⁴ groups are optionally taken together withthe nitrogen to which they are attached to form a 3-8 memberedmonocyclic or a 7-12 membered bicyclic ring system, each optionallycomprising one or more additional heteroatom groups selected fromO(oxygen), S(O)_(z), and NR_(c), wherein each ring system is optionallysubstituted with one or more R_(d); each R_(c) is independently selectedfrom the group consisting of hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl,(C₁-C₆)alkylsulfonyl, arylsulfonyl, (C₁-C₆)alkylC(O)—, arylC(O)—,hydroxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, heterocycle,(C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylaminocarbonyl, and arylaminocarbonyl;each R_(d) is independently halo, cyano, nitro, oxo,R_(f)R_(g)N(C₁-C₆)alkyl, —CH₂)_(n)NR_(f)R_(g), —C(O)NR_(f)R_(g),—NR_(e),C(O)R_(g), arylC(O)NR_(f)R_(g), —C(O)OH, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, —(CH₂)_(n),OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₁-C₆)alkylC(O)—, (C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylC(O)O—, heterocycle,aryl, heterocycle(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —NR_(e),S(O)_(z)(C₁-C₆)alkyl, —NR_(e),S (O)_(z),aryl, —NR_(e),C(O)NR_(f)R_(g),—NR_(e),C(O)OR_(f), or —OC(O)NR_(f)R_(g); each R_(e) is independentlyhydrogen, (C₁-C₆)alkyl, aryl or heteroaryl; each R_(f) and R_(g) isindependently hydrogen, (C₁-C₆)alkyl, aryl or heteroaryl, or R_(f) andR_(g) are optionally taken together with the nitrogen to which they areattached to form a 3-8 membered monocyclic or a 7-12 membered bicyclicring system, each optionally comprising one or more additionalheteroatom groups selected from O(oxygen), S(O)_(z), and NR_(c) whereineach ring system is optionally substituted with one or more R_(q); eachR_(q) is independently halo, cyano, nitro, oxo, —NR_(i)R_(j),R_(i)R_(j)N(C₁-C₆)alkyl, —(CH₂)_(n)NR_(i)R_(j), —C(O)NR_(i)R_(j),—NR_(k)C(O)R_(j), arylC(O)NR_(i)R_(j), —C(O)OH, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, —(CH₂)_(n),OH, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₁-C₆)alkylC(O)—, (C₁-C₆)alkylOC(O)—, (C₁-C₆)alkylC(O)O—, heterocycle,aryl, heterocycle(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —NR_(e)S(O)_(z)(C₁-C₆)alkyl, —NR_(k)S(O)_(z),aryl, —NR_(k)C(O)NR_(i)R_(j),—NR_(k)C(O)OR_(i), or —OC(O)NR_(i)R_(j); each R_(k) is independentlyhydrogen, (C₁-C₆)alkyl, aryl or heteroaryl; each R_(i) and R_(j) isindependently hydrogen, (C₁-C₆)alkyl, aryl or heteroaryl; and the dashedline represents an optional double bond wherein the ring comprising A¹,A², and A³ is heteroaromatic; with the proviso that when Y is —N(R⁴)₂,then R⁴ is not a 7-azabicyclo[2.2.1]heptane or1-azabicyclo[2.2.2]octane, each optionally substituted with(C₁-C₆)alkyl, with the proviso that the compound of formula I is not:

and a pharmaceutically acceptable excipient or carrier.